By Ralph Sanchez, L.Ac.CNS,D.Hom.

One of the longest held thoughts about damage to our brain’s cells (neurons) was that once they were lost, it was a fait accompli. Damaged neurons were considered damaged goods, never to regain their function, and without any hope for regeneration. Fortunately, for those concerned about recovery from brain trauma, stroke, and the neurological damage associated with Alzheimer’s disease (AD), there is promising research indicating that growth factors in the brain, not only promote brain structure and function associated with memory and learning, they can promote brain growth and recovery from damaging events to the brain.

Brain Derived Neurotrophic Factor

Growth factors comprise a varied family of proteins and hormones that regulate and control cellular growth and differentiation (cell division). In the brain, nerve growth factors (neurotrophins) have recently been discovered to play a vital role in neuronal growth, development and survival. In the brain, neurotrophins are vital signaling molecules * that regulate the function and structure of connective junctures (the synapse) between brain cells (neurons), and the processes that lead to learning and memory formation.

Promising research is emerging around one particular neurotrophin-Brain-derived neurotrophic factor ** (BDNF), in Alzheimer’s disease and other neurological disorders. BDNF, one of 4 identified neurotrophins ***, was originally first identified in the brain.  It was later found in the peripheral nervous system and other tissues. In the brain, BDNF is normally produced in the entorhinal cortex, the hippocampus, and other vital areas of the brain (cerebrocortex) where memory and learning are facilitated.

How important is BDNF? In studies, the inhibition of BDNF and Neural Growth Factor (NGF) to neurons stimulates the molecular events typical of the AD process. Amyloid beta (AB), the protein that accumulates and aggregates into the plaque lesions of AD, is increased in a neuronal environment of BDNF and NGF deprivation. The interruption of BDNF and NGF signaling sets forward the toxic mechanisms that induce the death and loss of neurons. (1) On the other hand, evidence is mounting indicating that augmentation of neurotrophic factors, BDNF and Nerve Growth Factor (NGF), prevent or reduce the loss of neurons in Alzheimer’s disease models. (1)

One of the most promising interventions for rescuing cognitive function in AD is neural stem cell therapy. Stem cell treatment portends to be the proverbial cure for the loss of memory and cognitive function related to neurological disease. Neural stem cell transplantation can restore cognitive function in neurological diseases like AD. In animal research, stem cell therapy restored cognitive function in mice that exhibited the typical lesions associated with AD. In spite of the extensive plaques and tangles present, stem cell transplantation restored memory and spatial learning **** to aging mice via BDNF mediated increases on hippocampal synaptic density.***** (2)

The Synapse

In the brain, BDNF promotes the optimum communication between neurons by enhancing “plasticity” at the synapse (see illustration below). In my article on the role of insulin in brain and synaptic plasticity, I described brain plasticity, as “the brain’s malleability-its capacity for adaptive change”. This adaptive capacity by the brain is reflected in the ability to integrate information and experiences, and through higher cognitive processing, anchor them into learning and memory formation.

The synapse is a critical locus in this adaptive capacity. The integration of learning and subsequent memory formation, and the plasticity that enhances that process, is reflected and promoted by the formation of new synapses that extend the network of communication, and the strength** of the synaptic connection. BDNF plays an important role in the survival of neurons, their growth (axons and dendrites), and the formation and function of the synapse. (2) Without sufficient BDNF and other neurotrophic factors, neurons die. (3)

The synapse is a crucial messaging exchange center between neurons. Synaptic junctions between neurons are where the cell-to-cell brain circuitry is facilitated. This complex neural circuitry and its growth and development, is what facilitates learning and memory formation. BDNF is key in both the growth and formation of the network of synapses, and the signaling mechanisms that underlies synaptic function and plasticity. (2) Since the role of BDNF is essential in the structural and functional elements integral to learning and memory formation, it has become a research target in its potential role in mitigating the degenerative process associated with AD and other neurological disorders.

BDNF & Alzheimer’s disease

To summarize some points made above, BDNF levels are the highest in the areas of the brain associated with memory and learning. The deprivation of neurotrophic factors, BDNF and NGF, leads to the development of AD. Lack of BDNF signaling at the synapse, is a link in the cascade of amyloid beta formation that leads to the toxic aggregation and plaque lesions associated with AD. (Please read my article on Amyloid Plaque & Tangles).

Until recently, the research to date on the role of BDNF in AD risk has centered on laboratory cultures of hippocampal and other brain tissues. Now, a recent animal study (2/2009) at the University of California, San Diego (UCSD), affirms the promising role of BDNF in the prevention, and the possible reversal of neuronal degeneration, and cell death, associated with AD. (4) Memory loss, cognitive impairment, brain cell degeneration, and cell death were prevented or reversed in several animal models after treatment with BDNF. The UCSD study treated animals had widespread lesions associated with AD (plaques & tangles). Despite the cognitive impairment present, BDNF treatment improved the performance of impaired animals in a variety of learning and memory tests, as compared to control groups not treated with BDNF.

The UCSD study on the role of BDNF in AD is particularly significant as it showed that BDNF treatment might potentially provide long-lasting protection by slowing, or even stopping, the progression of Alzheimer’s disease. Mark Tuszynski, M.D., Ph.D., professor of neurosciences at the U.C. San Diego School of Medicine, reported: “When we administered BDNF to memory circuits in the brain, we directly stimulated their activity and prevented cell death from the underlying disease.”

Optimizing BDNF

Optimizing BDNF in the brain can provide two essential benefits for brain health:

•    Enhance cognitive function, and

•    Protect your brain from the degenerative processes associated with aging, as well as the neurological decline that marks AD.

The good news is that there are core nutrition and lifestyle factors that directly influence BDNF levels and benefits to the brain.  Numerous studies demonstrate the benefit of exercise on cognitive function in healthy individuals, as well as those afflicted with AD (see video below). Nutrition and stress also mediate a significant impact on the risk for AD. In related research, it is shown that these same factors influence BDNF levels and function.

In my next article on BDNF, I will delineate more on these nutrition and lifestyle factors, and their influence on optimizing BDNF, and how key nutraceuticals can also enhance BDNF in the brain.

For those of you reading this article at another website other than TheAlzheimersSolution.com, please visit the Neurotrophic Factors category at TheAlzheimersSolution.com.

* Signaling molecules…chemical messengers that serve to transmit information between cells.

** Neurotrophic factors–derived from the Greek “neuro” for nerve and “troph” for nourish.

*** The family of neurotrophins includes BDNF, Neural Growth Factor (NGF), Neurotrophin-3 (NT-3) and Neurotrophin-4 (NT-4)

**** Spatial learning…implies the ability to orient oneself in relation to their environment

***** Synaptic density: the number of connections via synaptic junctions between neurons

****** Synaptic strength…the established ease of communication across the synapse (between neurons).
The repetitive and frequent stimulation of the neuron in a learning process establishes synaptic strength-i.e. learning how to write, or play an instrument, strengthens the neural pathway, and establishes the synaptic strength between neurons.

References

1. NGF and BDNF signaling control amyloidogenic route and Aβ production in hippocampal neurons

Carmela Matrone, Maria Teresa Ciotti, Delio Mercanti, Roberta Marolda*, and Pietro Calissano

PNAS  September 2, 2008   vol. 105  no. 35  13139-13144

2. Neural stem cells improve cognition via BDNF in a transgenic model of Alzheimer disease

Mathew Blurton-Jonesa,Masashi Kitazawaa,Hilda Martinez-Coriaa, Nicholas A. Castelloa, Franz-Josef Müllerb, Jeanne F. Loring, Tritia R. Yamasakia, Wayne W. Poona, Kim N. Greena and Frank M. LaFerla

PNAS  August 11, 2009   vol. 106  no. 32  13594-13599
http://www.pnas.org/content/106/32/13594.abstract

3. Role for brain-derived neurotrophic factor in learning and memory.

Yamada K, Mizuno M, Nabeshima T.

4. Neuroprotective effects of brain-derived neurotrophic factor in rodent and primate models of Alzheimer’s disease.

Nagahara AH, Merrill DA, Tuszynski MH, et al.

Nat Med 2009; E-pub 2009 Feb 8.

By Ralph Sanchez, L.Ac.,CNS,D.Hom

Long before a diagnosis of Dementia or Alzheimer’s disease (AD) is given, brain damage is occurring that leads to, and reflects the gradual downward spiral of mental decline that typifies AD. A cluster of signs that define Mild Cognitive Impairment (MCI), especially memory loss and forgetfulness, may be the early warning indicators that you are at risk for developing AD. If you can visualize a spectrum whereby healthy brain/cognitive function in an individual is on one side of the spectrum, and AD is on the opposite side, MCI would be inching ever so close to the AD side of the spectrum. The individual with MCI is more functional than one who is clinically diagnosed with dementia, albeit with MCI, there is subtle to noticeable problems with memory, judgment, language and other cognitive skills. These symptoms, along with other criteria that define MCI, are now recognized as the transitional stage of brain degeneration that may lead to Dementia and AD. (1)

In essence, MCI often represents cognitive decline that reflects degenerative brain processes that is beyond normal aging, but precedes more severe deterioration and diagnosis of dementia. (2) What has been generally accepted to be normal age-related cognitive decline, may represent to some degree, damage or degenerative processes to brain tissue. A recent study (2006) concluded that the underlying brain deterioration in memory loss related MCI (see classifications of MCI below), represented the early stages of AD brain damage. (3) Autopsies of individuals in this study, revealed the same characteristic brain lesions, neurofibrillary tangles and beta-amyloid plaque, associated with AD.

Whether self reported or observed by a physician, the typical memory loss, or other cognitive impairment, needs to be differentiation from other disorders including depression, drug side effects, and hormonal or nutritional imbalances. Unfortunately, MCI as an early indicator of an advanced risk for developing AD is not assessed routinely in patients that present with memory lapses, or other cognitive problems. Senior moments are often written off as normal age-related memory loss. Due to this fact, a large proportion of patients with MCI may remain undiagnosed until the cognitive decline is more noticeable, or advanced signs of frank dementia or AD are obvious.

In the early stages, MCI may appear or be interpreted as normal aging by either the individual that is affected, those close to him or her, or to the untrained professional. Fortunately, due to the increased awareness of the Alzheimer’s issue in the aging population, many individuals are now expressing concern to their physicians about memory loss. Indeed, the early detection of cognitive problems that represent the early signs of MCI is critical for preventing the progression to, or at the very least, delaying the development of AD.

The problem in diagnosing MCI lies in part with the fact that in the past, cognitive decline in an aging individual was often classified as degeneration associated with a normal aging process. MCI, and its subtypes, is a more recent construct and classification of cognitive impairment, that represents a nuerodegenerative disease process. (4) Prior to the emergence of MCI, and MCI subtypes, as a diagnosable clinical entity, terms such as “benign senescent forgetfulness” and “age-associated memory impairment” (AAMI) were the default labels given to those aging individuals that presented with memory loss. Granted, there is still some resistance, and flat rejection of MCI as a clean window of assessment for a neurodegenerative disease process. (5) Yes, not all diagnosed with MCI progress to dementia or AD. It is not uncommon for a less severe form of MCI (single domain nonamnestic subtype) to revert back to normal. (6) However, the consensus is growing toward the point of this article; the diagnosis of MCI, especially at first signs, may provide the opportunity for prevention of a more serious degenerative disease process. There is now significant and inarguable evidence that demonstrates that MCI can be assessed and identified by objective and measurable testing such as specialized PET scans and MRIs.

Again, the conversion of MCI to AD in any individual will be influenced by a host of factors. Lifestyle, nutrition, stress, education, hormonal factors and genetics will weigh heavily into whether or not one progresses from MCI to dementia or AD. These same factors are the modifiers that determine if a person diagnosed with MCI can delay or prevent the conversion to dementia and AD, or in less complicated cases, revert back to normal. Optimizing brain nutrition can be one of the most powerful interventions for stabilizing and improving brain function.

Types of MCI

The early stages of MCI in an individual appear as subtle changes that may not always be noticeable, unless observed by a trained professional, or by a family member or friend that is close to that person. Individuals in the early stages of MCI are functional and will compensate for some impairment by making lists and notes to support daily activities and responsibilities. Independence can actually be maintained for years.

Signs that may signal the onset of MCI are:

•    Memory loss – recent recall diminishes, such as what one did yesterday, repeatedly misplacing objects

•    Language - difficulty communicating…inability to recall and integrate words into a conversation, or to follow one

•    Visuospatial ability – placement of things in time and space becomes more difficult – i.e. having trouble getting the proportions right when drawing a box

•    Executive function - difficulty with decision making, planning and organizing

These patterns of cognitive dysfunction have recently been categorized into MCI subtypes.

MCI is differentiated into two basic subtypes:

•    amnestic MCI and…
•    non-amnestic MCI

Amnestic MCI is defined as MCI with memory loss, while non-amnestic MCI represents MCI with little or no memory loss, but with other cognitive function impairment (language, visuospatial ability, executive function).

Similarly, in what is considered to be a subtype of amnestic MCI, multiple cognitive domain amnestic-MCI, may include memory loss and the other domains of impairment associated with non-amnestic MCI (visuospatial ability, judgment and language problems – see chart below).

Besides having little or no memory loss associated with it, non-amnestic MCI (single domain), and its subtype, non-amnestic multiple cognitive domain-MCI, includes problems with visuospatial ability, judgment (executive function), or language. (3) If the non-amnestic MCI presents with only a single area of impairment, then it is classified as single cognitive domain non-amnestic MCI.

So we have the two basic subtypes of MCI, amnestic MCI and non-amnestic MCI, and two additional subtypes:

•    amnestic MCI and…
•    amnestic MCI-multiple cognitive domain
or
•    non-amnestic MCI-single cognitive domain and…
•    non-amnestic MCI-multiple cognitive domain

Either type of MCI can convert to a dementia diagnosis (. i.e. vascular dementia) or AD, and the classifications may serve to predict the probability of conversion to AD, or the type of dementia that an individual diagnosed with MCI is at risk for. Several studies indicate a higher conversion for amnestic MCI to AD. (7) The greater memory loss, the more severe the impairment may be, and the higher the risk for the impairment progressing to AD.

Cardiovascular disease and diabetes are risk factors for AD. Not surprisingly, these same degenerative disorders, are linked to MCI as well (comorbid conditions). In a significant and large population–based Study of Aging conducted at Mayo clinic, patients with history of stroke (cerebrovascular disease) were found to have higher (three times) risk of non-amnestic MCI. Diabetics that had a more advanced form of the disease, doubled their chances for non-amnestic MCI. Similarly patients with other vascular diseases like hypertension and coronary heart diseases were found to be at higher risk of having non-amnestic-MCI. (8) Some research indicates a more likely progression to vascular dementia from non-amnestic-MCI. Similarly, non-amnestic-MCI is associated with the conversion to frontotemporal dementia and dementia with Lewy bodies. (9) Again, individuals with amnestic-MCI are thought to be more likely converters to AD.

ApoE4/MCI

The ApoE4 gene variant (please read article: The Alzheimer’s Gene Puzzle – Genetic Links To Late Onset Alzheimer’s Disease-Part 1), a risk factor for AD in and of itself, is linked to MCI and the conversion of MCI to AD as well. Carriers of the ApoE4 gene (genotypes) are more likely to develop amnestic MCI, and ApoE4 genotypes diagnosed with amnestic MCI patients are more likely to progress to AD. (10) Not a surprising link. It is my strong recommendation that if you are diagnosed with MCI, to have an ApoE gene test done. Anyone with MCI, especially amnestic MCI, and who is a carrier of the ApoE4 variant, should have an aggressive dietary, lifestyle and nutritional plan implemented immediately. If it is not part of the current history, assessments for inflammation and oxidative stress should be integrated into a complete health evaluation. Antioxidants have demonstrated in clinical studies to protect and delay progression of AD in at risk individuals. Key nutrients that are important factors in brain health and that are linked to a greater risk for developing AD and/or dementia if deficient, are folate, B12, Vitamin D, and Vitamin K. Antioxidants and a host of other brain function supportive nutraceuticals such as Acetyl-L-Carnitine, and Phosphatidyl Serine, should also be considered for supplementation. Thyroid function, as well as estrogen and testosterone levels should be checked.

Undoubtedly, the exclusion of, or the definitve diagnosis of MCI, particularly in more at risk individuals with memory and cognitive problems, should be determined as early as possible. Fortunately, there is technology now available that can alert providers and their at risk patients, as to how large that risk may be for conversion of MCI to AD.  Please look for my coming articles that overview on how you can screen for the underlying brain damage that is occuring in MCI, and the important nutrients that can help to preserve your vital brain.

This video below from a HBO documentary, “The Alzheimer’s Project: Identifying Mild Cognitive Impairment”, is highly recommended.

For those of you reading this article at another website other than TheAlzheimersSolution.com, please visit the Mild Cognitive Impairment category at TheAlzheimersSolution.com.

References:

1. Mild cognitive impairment represents early-stage Alzheimer disease.

Morris JC, Storandt M, Miller JP, McKeel DW, Price JL, Rubin EH, Berg L.

Arch Neurol. 2001 Mar;58(3):397-405.

2. Behavioral neurology in the elderly

Authors: José León-Carrión, Margaret Joan Giannini

3. Neuropathologic substrate of mild cognitive impairment.

Markesbery WR, Schmitt FA, Kryscio RJ, et al.

Arch Neurol. Jan 2006;63(1):38-46

4. Mild Cognitive Impairment: An Overview

Ronald C. Petersen, MD, PhD, and Selamawit Negash, PhD

CNS Spectr. 2008;13(1):45-53

5. Mild Cognitive Impairment Is Not a Clinical Entity and Should Not Be Treated

Gauthier and Touchon

Arch Neurol.2005; 62: 1164-1166.

6. Quantification of Five Neuropsychological Approaches to Defining Mild Cognitive Impairment

Jak, Amy J. Ph.D.; Bondi, Mark W. Ph.D.; Delano-Wood, Lisa Ph.D.; Wierenga, Christina Ph.D.; Corey-Bloom, Jody M.D., Ph.D.; Salmon, David P. Ph.D.; Delis, Dean C. Ph.D.

American Journal of Geriatric Psychiatry. May 2009 – Volume 17 – Issue 5 – pp 368-375

7. Importance of Subtle Amnestic and Nonamnestic Deficits in Mild Cognitive Impairment: Prognosis and Conversion to Dementia

S.D. Rountree, S.C. Waring, W.C. Chan, P.J. Lupob, E.J. Darby, R.S. Doody

Dement Geriatr Cogn Disord 2007;24:476-482
8. The Mayo Clinic study of aging: Incidence of mild cognitive impairment

R. Petersen, R. Roberts, D. Knopman, Y. Geda, V. Pankratz, B. Boeve, W. Rocca

Alzheimer’s and Dementia, Volume 4, Issue 4, Pages T130-T130
9. Mild Cognitive Impairment preceding dementia with Lewy Bodies.

Boeve B, Ferman TJ, Smith GE, et al.

Neurology. 2004;62(suppl 5):A86.
10. Mild cognitive impairment.

Gauthier S, Reisberg B, Zaudig M, Petersen RC, Ritchie K, Broich K, Belleville S, Brodaty H, Bennett D, Chertkow H, Cummings JL, de Leon M, Feldman H, Ganguli M, Hampel H, Scheltens P, Tierney MC, Whitehouse P, Winblad B; International Psychogeriatric Association Expert Conference on mild cognitive impairment.

Lancet. 2006 Apr 15;367(9518):1262-70.

By Ralph Sanchez, L.Ac.,CNS,D.Hom.

Alpha lipoic acid (ALA), a naturally occurring nutrient found in many foods and available in supplemental form, is also synthesized in humans where it serves in energy metabolism and as a vital antioxidant. ALA is a unique antioxidant in that it is both water and fat-soluble, which enables ALA to confer its antioxidant benefits to all the cells and cell structures of the body. Another important characteristic of ALA is that it is part of the antioxidant team that includes vitamin E, C, coenzyme Q10 and glutathione. ALA regenerates theses antioxidants as they are metabolized in their protective antioxidative roles. As an antioxidant, the protective benefits of ALA are well documented in the research literature. However, just this month (12-08), scientists have been able to describe some of the mechanisms behind ALA’s brain protective (neuroprotective) function with respect to peroxynitrite, (1) a potent oxidant,* nitrative agent** and pro-inflammatory molecule that induces cellular damage and death (apoptosis). (2) Peroxynitrite mediates its toxic effects by reacting with structural and functional proteins and fats of the cell, as well as its DNA.

DNA Helix

Peroxynitrite’s damage to DNA is induced by “strand breaks”. There are many forms of DNA damage with double-strand breaks (DSBs) being the most severe. Single strand breaks are an easier fix for the repair mechanisms involved in DNA maintenance. Recall the strand double helix image of DNA from your science class? Well now picture it being broken…that is a strand break (see images below), and peroxynitrite mediated damage is one of the mechanisms responsible for your DNA malfunctioning, and the toxic pathways that leads to brain cell (neurons) damage and death. (3) Most vulnerable is the DNA of the cell’s mitochondria. Mitochondrial DNA is more susceptible to toxic insults, and once this cellular energy factory is overwhelmed by peroxynitrite-mediated reactions, the eventual demise of the brain cell is not far behind. (4) Besides DNA damage, peroxynitrite elevations in the brain is linked to neurofibrillary tangles (5), and the neurotoxicity of beta-amyloid peptide (BAP). (6) The oxidative stress induced by peroxynitrite and other oxidative factors, is a key component to the disease process associated with Alzheimer’s disease. (7)

The role of ALA in buffering the neurotoxic effects of peroxynitrite is a recent revelation, yet there is plenty of similar evidence demonstrating the same benefits to other antioxidants-both from foods and nutraceuticals. Glutathione, the body’s primary antioxidant, counters peroxynitrite reactions, and protects against DNA single strand breaks. (8) Carotenoids (lycopene, beta-carotene) and ascorbates (vit C as mineral ascorbates) are able to neutralize peroxynitrite oxidation. (9) Quercetin and EGCg from green tea, rutin, and resveratrol and cocoa have neuroprotective benefits including protection from peroxynitrite. (10, 11) Ellagic acid in strawberries, blueberries and raspberries are protective from oxidative and nitrative damage from peroxynitrite. (12) Grape Seed Polyphenols*** have also demonstrated in research to have peroxynitrite scavenging properties, (13) inhibition of beta amyloid plaque formation, and the protection from other oxidative stress reactants associated with beta amyloid toxicity on brain cells. (14, 15)

A diet rich in these natural antioxidants as well as supplementing with a blend of these nutraceuticals will provide invaluable protection to your brain and the rest of your body as well. The pathways of oxidative stress and nitrative stress, require antioxidants that are effective scavengers for the varying oxidative or nitrative reactions. For examples of these types of formulations (i.e. Detox Antiox, Quercetin + Nettles, Resveratrol Synergy), please visit the Antioxidant section of TheAlzheimersSolution.com.
Note that it links you to my Health and Wellness store @ FunctionalHealthSolutions.com.
http://cat.inist.fr/?aModele=afficheN&cpsidt=1310376

* Oxidant: A substance (i.e. peroxynitite) that is capable of oxidizing another substance through oxygen mediated reactions. In the process, the oxidizing agent (i.e. peroxynitite) accepts electrons and the oxidized substance loses electrons. Oxidation is a normal component of energy metabolism and immune system defenses. However, in the case of certain oxidants like peroxynitrite, the reactions taking place are at the expense of cellular structures and DNA, as well as mitochondrial DNA.

** Nitration: Just as the biochemical reactions of oxidation are a potentially damaging process in the body, nitration also can exert ” Nitrative Stress”. The same proteins, lipids, and cellular DNA damaged by oxidative reactions, are also mediated by nitrative reactions. “Oxidative Stress” involves reactions mediated by oxygen containing molecules, while “Nitrative Stress” involves reactions mediated by nitrogen containing molecules.
Note: Peroxynitrate (ONOO) contains both oxygen and nitrogen compounds and is a potent oxidation and nitration agent.

*** Oxidative Stress: Oxidative stress is a physiological condition whereby there is an imbalance between protective antioxidants and oxidative free radicals and other oxidants. The “oxidative balance” between antioxidants and the free radicals and oxidants that they quench, is a key element in optimizing health and buffering against the aging process and some of the degenerative diseases associated with it.

**** Polyphenols: Plant chemicals (phytochemicals) that function as antioxidants. They are found in wine, tea, chocolate, and some fruits and vegetables.

1. Alpha-lipoic acid potently inhibits peroxynitrite-mediated DNA strand breakage and hydroxyl radical formation: implications for the neuroprotective effects of alpha-lipoic acid.
Jia Z, Zhu H, Vitto MJ, Misra BR, Li Y, Misra HP.
Mol Cell Biochem. 2008 Dec 11.

2. Peroxynitrite-induced cytotoxicity: mechanism and opportunities for intervention
L Virág, E Szabó, P Gergely, C Szabó
Toxicol Lett (2003) 140: 113-24.

3. Apoptosis and necrosis: two distinct events induced, respectively, by mild and intense insults with N-methyl-D-aspartate or nitric oxide/superoxide in cortical cell cultures
E Bonfoco, D Krainc, M Ankarcrona, P Nicotera, and S A Lipton
Proc Natl Acad Sci U S A. 1995 Aug 1;92(16):7162-6.

4. Peroxynitrite reactions and formation in mitochondria.
R Radi, A Cassina, R Hodara, C Quijano, L Castro
Free Radic Biol Med (2002) 33: 1451-64.

5. Alzheimer-like tau modifications and accumulation in rat brain and its underlying mechanisms.
Zhang, Y-J., Xu, Y-F., Liu, Y-H., Yin, J., Li, H-L., Wang, Q., Wang, J-Z.
FASEB J. 20, 1431–1442 (2006)

6. Peroxynitrite mediates neurotoxicity of amyloid beta-peptide1-42- and lipopolysaccharide-activated microglia.
Xie Z, Wei M, Morgan TE, Fabrizio P, Han D, Finch CE, Longo VD.
J Neurosci. 2002 May 1;22(9):3484-92.

7. Widespread Peroxynitrite-Mediated Damage in Alzheimer’s Disease
Mark A. Smith, Peggy L. Richey Harris, Lawrence M. Sayre, Joseph S. Beckman, and George Perry
J. Neurosci., April 15, 1997, 17(8):2653–2657

8. Selenium-Containing Compounds Protect DNA from Single-Strand Breaks Caused by Peroxynitrite
Ivan Roussyn, Karlis Briviba, Hiroshi Masumoto and Helmut Sies 1
Archives of Biochemistry and Biophysics Volume 330, Issue 1, 1 June 1996, Pages 216-218

9. Effect of lycopene and beta-carotene on peroxynitrite-mediated cellular modifications.
Muzandu Kaampwe, Ishizuk, Mayumi, Sakamoto Kentaro Q.
Shaban Zein, Bohi Khlood El, Kazusaka Akio, Fujita Shoichi
Toxicology and Applied Pharmacology. 215(3), 2006, 330-340

10. Protection of peroxynitrite-induced DNA damage by dietary antioxidants.
Hye Kyung Moon, Eun Sun Yang, and Jeen Woo Park
Arch Pharm Res Vol 29, No 3, 213-217, 2006

11. Protection against peroxynitrite by cocoa polyphenol oligomers
G . Arteel                                                                                                                       FEBS Letters , Volume 462 , Issue 1 – 2 , Pages 167 – 170
12. Prevention of peroxynitrite-induced oxidation and nitration reactions by ellagic acid
Katsunari Ippoushi, Atsuko Takeuchi, and Keiko Azuma
Food Chemistry. Volume 112, Issue 1, 1 January 2009, Pages 185-188

13. Procyanidins from grape seeds protect endothelial cells from peroxynitrite damage and enhance endothelium-dependent relaxation in human artery: new evidences for cardio-protection
Giancarlo Aldini, Marina Carini, Angela Piccoli, Giuseppe Rossoni and Roberto Maffei Facino
Life Sciences. Volume 73, Issue 22, 17 October 2003, Pages 2883-2898

14. Effects of Grape Seed-derived Polyphenols on Amyloid β-Protein Self-assembly and Cytotoxicity
Kenjiro Ono, Margaret M. Condron, Lap Ho, Jun Wang, Wei Zhao, Giulio M. Pasinetti, and David B. Teplow
J. Biol. Chem., Vol. 283, Issue 47, 32176-32187, November 21, 2008

15. Grape-Derived Polyphenolics Prevent A-beta Oligomerization and Attenuate Cognitive Deterioration in a Mouse Model of Alzheimer’s Disease
Jun Wang, L. Ho, W. Zhao, K. Ono, C. Rosensweig, L. Chen, N. Humala, D.B. Teplow, G.M. Pasinetti
Journal of Neuroscience. June 2008, Volume 28, Pages 6388-6392

By Ralph Sanchez, L.Ac.,CNS,D.Hom

Insulin fulfills an indispensable role in your body’s utilization of blood sugar (glucose). In type 2 diabetes and Metabolic Syndrome, insulin’s function of glucose uptake into the body’s cells is impaired due to a resistance to insulin that develops over time. This insulin resistance pattern which defines the disease process of the above mentioned disorders, is now seen as a link to the degenerative spiral that occurs in Alzheimer’s disease (AD) over and above the role of insulin in glucose metabolism in the brain. Insulin resistance and its role in inflammation, and impaired insulin function in the brain are now understood to be underlying pieces of the Alzheimer’s puzzle.

Insulin Function In the Brain

The brain’s consumption of glucose is critical to fueling the high-energy machinery of its cells (neurons). This uptake of glucose into brain cells was formerly thought to transpire without the aid of insulin. However, it is now established that insulin’s function for neuron uptake of glucose is an important component of brain glucose metabolism. (1) If the uptake of glucose into the neurons is diminished, energy metabolism is hindered with significant consequences to the brain’s capacity to generate the connections vital to memory and learning. (2) Studies utilizing brain scans demonstrate the decreased brain metabolism of glucose in normal individuals that eventually go on to develop cognitive impairment or dementia. (3) Furthermore, there is now evidence that demonstrates insulin and it’s receptors in the brain as key elements to memory formation and learning beyond its function for glucose uptake. (4)

The Synapse

Insulin binds to receptors at the synapse, a key communication locus between neurons in the brain. Synaptic junctures between neurons is where the cell-to-cell brain circuitry is facilitated. Insulin is now known to serve as a vital element for synapse maintenance (structure and function) and subsequently for the strength of connections between neurons. (5) This insulin/synaptic axis and the formation of new circuitry in the brain, is a key contributor to “brain plasticity”. Brain plasticity refers to the brain’s malleability-its capacity for adaptive change. It is the brain’s ability to integrate change associated with learning, organize that experience and form new connections (synaptic density)* between brain cells that supports and enables that process. These processes occur throughout a person’s lifetime…as a young brain grows and develops, or as it recovers from brain trauma. The brain forms new connections and it “rewires” itself to integrate new information, as in a learning process, or it “rewires” itself to replace damaged pathways lost in a stroke. If insulin’s function in the brain is disrupted, synapse function and density is diminished and the neural pathways that optimize and reflect learning and memory formation are hindered. Decreased synaptic density and brain plasticity is a central feature of AD and disrupted insulin function at the synapse is largely to blame. So what causes insulin function in the brain to go awry and eventually contribute to adverse changes in brain function associated with AD? It has been largely postulated that amyloid plaque and neurofibrillary tangles, and you can pick your poison, were the primary and underlying processes that explained the loss of cognitive function associated with AD. Now we have more illuminating evidence that the cognitive impairment typical of AD begins prior to plaques and tangles accumulating. Amyloid-Beta Derived Diffusible Ligands (ADDLs) and their interaction with insulin

ADDLs

Insulin resistance and the associated inflammation that typifies type 2 diabetes/Metabolic Syndrome, is linked to increased beta- amyloid protein** (BAP) production and deposition in the brain. (7) The build up of BAP and the subsequent accumulation of amyloid plaques, has been theorized to be the central (please read my article on Plaques and Tangles) process associated with the degeneration in AD. However, more recent studies have demonstrated that a probable precursor to insoluble amyloid plaques, ADDLs, are thought to be more toxic than the amyloid plaques they eventually form, and largely responsible for the cognitive deficits that occur in AD. (10) In AD, insoluble plaque formation is preceded by the production of Amyloid-Beta Derived Diffusible Ligands (ADDLs). ADDLs are small, soluble aggregated proteins, which are gaining acceptance as the primary mediators of the neurodegeneration associated with AD before the aggregation and deposition of insoluble amyloid plaque.

Insulin/ADDLs

One of the damaging effects of ADDL formation in the brain is its impact on insulin levels and function. In part, ADDLs do their damage by binding at the synapse and triggering the loss of insulin and synapse function. ADDLs are thought to prevent insulin receptors from accumulating at the synapse and effectively making them unable to respond to insulin and thus insulin resistant. (11) This loss of insulin function in AD is described by several researchers as a brain specific “type 3 diabetes”. The insulin/ADDL pivot in AD is certainly a component that represents another important piece in the AD puzzle.

Insulin/Inflammation

Elevated insulin patterns that underlies Type 2 diabetes and Metabolic Syndrome, is linked to inflammatory processes. (6) This pro-inflammatory milieu associated with many other disorders as well, has the potential to spur inflammation in the brain and increase the risk for AD. (7) Abdominal fat stores and obesity that are hallmark signs of type 2 diabetes/Metabolic Syndrome also contribute to the inflammatory cascade and raises the risk for AD and dementia. One large study conducted by Kaiser-Permanente in Northern California concluded that belly fat at middle age could almost triple the risk of dementia later in life. (8)

Apart from the pro-inflammatory effects of elevated insulin levels in AD, elevated insulin poses another problem. Insulin in the brain is degraded by insulin degrading enzyme (IDE). IDE also degrades toxic amyloid plaque. Insulin has a very similar molecular structure to amyloid plaque and thus might compete for the benefits of IDE. (9) Elevated insulin levels are implicated in the brain cells’ failure to clear beta-amyloid. Compounding the insulin/beta-amyloid competition for IDE is the finding that indicates lower IDE levels in patients with AD. The takeaway? Excess insulin can increase the risk of AD by stimulating pro-inflammatory molecules in the brain, and by impeding the clearance of beta-amyloid.

Impaired Insulin Function In The Brain

To summarize, insulin levels and function in the brain are key elements in memory, learning and brain plasticity. Research shows that levels of brain insulin and its related receptors are lower in individuals with Alzheimer’s disease. Underlying this insulin/AD axis is the impact of ADDLs and their binding with insulin receptors at a crucial locus of memory and learning facilitation-the synapse. This disrupted insulin interaction (signaling) with receptors leads to the loss of synapse function vital to the connectivity between brain cells and a healthy brain that can learn and retain information.

Insulin is in part responsible for the uptake of glucose into the neuron. The human brain needs a great deal of glucose for energy metabolism and individuals who have a greater genetic risk (ApoE4) for AD have lower rates of glucose metabolism. Insulin resistance that underlies type 2 diabetes/Metabolic Syndrome contributes to decreased brain insulin levels (12), and elevated insulin in the body (periphery) contributes to inflammatory molecules in the brain. Indeed, elevated insulin in the body can have direct and deleterious consequences on brain integrity. However, as an emerging theory and explanation of the cascade of neurodegeneration that characterizes AD, the role of insulin function in the brain and how its dysregulation directly contributes to the cognitive impairment that defines AD, is now becoming a neuroendocrine model of AD that seems destined to replace the amyloid theory of AD.

As compelling as the role of insulin dysfunction and its link to a type 3 diabetes of the brain is in AD, it is important to bear in mind that the core elements that contribute to AD remain the same. Genetics, nutrition, lifestyle, toxins, inflammation, oxidative stress, mitochondrial dysfunction and hormonal factors like insulin, and estrogen, are all inextricably woven together in the fabric of the AD brain. There is not a single isolated entity in that fabric that we can hang our hat on and pronounce it as the holy grail of the AD cure. The insulin/synapse axis and its role in brain plasticity gives a more upstream and plausible model of AD that illustrates the cognitive decline inherent in AD before actual neurodegeneration occurs. (13) However, AD is a multifactorial disease process and it is my utmost conviction that only the careful evaluation of each person’s risk factors before they manifest into this disease, will ultimately reduce the growing health crisis that AD is becoming.

* Synapse density: percentage of synapses per cubic millimeter of tissue

** beta-amyloid protein is also referred to as amyloid beta or ABeta is produced from amyloid precursor protein and is the principal component of amyloid plaque found in Alzheimer’s as well as other neurological diseases.

1. Bingham EM, Hopkins D, Smith D. et al. The role of insulin in human brain glucose metabolism: an 18fluoro-deoxyglucose positron emission tomography study. Diabetes. 2002 Dec;51(12):3384-90.

2. Zhao WQ, Alkon DL.
Role of insulin and insulin receptor in learning and memory. Mol Cell Endocrinol. 2001 May 25;177(1-2):125-34.
3. C. C. Wu, BA, D. Mungas, PhD, C. I. Petkov, BS, J. L. Eberling, PhD. et al. Brain structure and cognition in a community sample of elderly Latinos. Neurology. 2002;59:383-391
4. Zhao WQ, Alkon DL. Role of insulin and insulin receptor in learning and memory. Mol Cell Endocrinol. 2001 May 25;177(1-2):125-34.
5. S. Chiu, C. Chen, H. Cline. Insulin Receptor Signaling Regulates Synapse Number, Dendritic Plasticity, and Circuit Function In Vivo. Neuron, June 11 2008, Volume 58, Issue 5, Pages 708 – 719

6. Steven E. Shoelson, Jongsoon Lee, and Allison B. Goldfine. Inflammation and insulin resistance. J Clin Invest. 2006 July 3; 116(7): 1793–1801.

7. Mark A. Fishel, G. Stennis Watson, Thomas J. Montine et al.
Hyperinsulinemia Provokes Synchronous Increases in Central Inflammation and -Amyloid in Normal Adults
Arch Neurol. 2005;62:1539-1544

8. Whitmer RA, Gustafson DR, Barrett-Connor E, Haan MN, Gunderson EP, Yaffe K. Central obesity and increased risk of dementia more than three decades later. Neurology. 2008 Mar 26.

9. Alafuzoff I, Aho L, Helisalmi S, Mannermaa A, Soininen H. beta-Amyloid deposition in brains of subjects with diabetes.
Neuropathol Appl Neurobiol. 2008 Mar 10

10. Catalano Susan M, Dodson Elizabeth C, Henze Darrell A. et al. The Role of Amyloid-Beta Derived Diffusible Ligands (ADDLs) in Alzheimer’s Disease. Current Topics in Medicinal Chemistry, Volume 6, Number 6, March 2006 , pp. 597-608(12)

11. Wei-Qin Zhao, Fernanda G. De Felice, Sara Fernandez, et al.
Amyloid beta oligomers induce impairment of neuronal insulin receptors. FASEB J. 2008 Jan;22(1):246-60. Epub 2007 Aug 24.

12. Craft, Suzanne PhD. Insulin Resistance Syndrome and Alzheimer Disease: Pathophysiologic Mechanisms and Therapeutic Implications.
Alzheimer Disease & Associated Disorders. 20(4):298-301, October/December 2006.

13. Dennis J. Selkoe. Alzheimer’s Disease Is a Synaptic Failure
Science 25 October 2002: Vol. 298. no. 5594, pp. 789 – 791

I will be starting a podcast on a regular basis.

This is a test to see how the system we’ve implemented is working.

By Ralph Sanchez, L.Ac.,CNS,D.Hom

Genetic risk factors to Late Onset Alzheimer’s Disease (LOAD) are significant. A recent study of nearly 12,000 Swedish twin pairs, age 65 and older, determined that 58% to 79% of Alzheimer’s risk is genetic (1). This study showed that in male identical twins, when one brother had Alzheimer’s disease, the other developed the disease 45% of the time. In female identical twins, when one sister had Alzheimer’s disease, the other developed the disease 60% of the time. While this study did not delve into specific gene influences in LOAD, numerous studies have identified Apolipoprotein E4 (ApoE4), as a prominent genetic risk factor for LOAD. About 25% of the population has one copy of the ApoE4 gene and individuals with the the ApoE4 gene are estimated to make up approximately 40%-80% of the Alzheimer’s disease population. (2)

As indicated by the Swedish Twin Study, gene influences are potent risk factors. In Alzheimer’s disease (AD) and in many other degenerative diseases, certain genes can increase your vulnerability to developing diseases associated with aging. Genes associated with AD and many other diseases, have a “normal” version and a “mutated” version, with the mutation of a single DNA base (called a SNP – pronounced snip) making the person more susceptible to developing a particular disease process. SNPs are not uncommon. Everyone has SNPs. They are what make up a person’s unique genetic blueprint. Think of a SNP like changing the color of one bead in a chain. The role of ApoE in AD is a good example of how SNPs affect disease development. Individuals with the ApoE4 variant, a SNP, have an increased risk of developing late-onset Alzheimer’s (3,4). Of course, some SNPs exert a stronger influence on diseases than others. In the early onset form of AD (EOAD), a rare hereditary form of AD affecting less than 10 percent of Alzheimer’s patients, three different SNPs in genes, beta Amyloid Precursor Protein, Presenilin1, and Presenilin 2 are deemed causative for developing early onset AD. In contrast, the ApoE4 gene, a SNP in the ApoE gene, is considered a susceptibility risk factor, not a determinant for developing LOAD.

Several genes have been linked to LOAD with the ApoE4 gene having the clearest association with amount of risk it concurs in individuals that carry that variant. (5) There are three variants of ApoE–ApoE2, ApoE3, and ApoE4. Everyone has two copies of ApoE genes with six possible combinations-ApoE2/2, ApoE2/3, Apoe2/4, ApoE3/3, ApoE3/4, ApoE4/4. Individuals who inherit at least one copy of the ApoE4 variant have an increased risk of at least double, and up to a 3 to 4 fold increased risk for developing LOAD. Similar research has shown that people who inherit two copies of ApoE4 have as much as a ten fold greater risk of developing this disease. (2) It is important to note however, that not all people with Alzheimer’s disease have the ApoE4 variant and not all people who have inherited the ApoE4 gene will develop Alzheimer disease. Nevertheless, SNPs are not to be overlooked in those individuals that want to implement a proactive preventive strategy for AD and other degenerative diseases associated with aging. Understanding one’s own genetic potential for AD and the enviromental risk factors that carry significant weight, can provide opportunities for positively exercising preventive measures. AD and most other diseases have a biological timeline of 10 to 20 years or more, before a diagnosis is made. Waiting for the first signs of cognitive impairment or until that diagnosis is given may also impair your efforts to take control over the best years of your life.

Most diseases of aging are influenced by gene-environment interactions. AD has both genetic and environmental risk factors. The genetic susceptibility influenced by genes like ApoE4 are factors to be aware of, but perhaps more important are the environmental risk factors. Environmental risk factors can act as triggers in the expression of gene potential.* Numerous studies indicate that ApoE4 carriers may be more vulnerable to environmental factors. Individuals with the ApoE 4 gene are less efficient at clearing mercury from the brain. Mercury exposures in those that are more susceptible to its toxic effects, can lead to the same degenerative processes associated with AD. (6) (See my mercury toxicity article). Other research has demonstrated that physical inactivity, drinking alcohol, smoking and a high intake of saturated fats increases the risk of dementia/AD overall but more so in those with the ApoE4 gene. (7) Stress patterns and the stress hormones that are a byproduct of that deleterious cycle also may contribute to the brain degeneration characteristic of AD. (8) ApoE4 in susceptible individuals could be a more significant increase risk for AD if there are lifestyle and stress issues that are lifelong patterns.

ApoE is not the only gene factor that raises the ante in LOAD. Emerging evidence indicates that other genes play a role in LOAD. The Mayo Clinic (Jacksonville) reported from a large study on first-degree relatives, that genes other than ApoE4 influence susceptibility to developing LOAD. In their report they noted that the gene for Insulin Degrading Enzyme (IDE) is likely a significant contributor to LOAD. Other research has identified the SORL1, BACE1, GAB2 and more recently, the CAHLM1 genes as significant risk factors as well. More on these genes and how they influence the risk for AD will be available soon in coming articles.

My e-book, The Alzheimer’s Solution, will be made available soon, and will provide you with a resource that will cover all you need to know about preventing Alzheimer’s disease. Please sign up to my email list and be among the first to be notified when it is released.

God Bless! Ralph Sanchez, L.Ac.,CNS,D.Hom.

* “Gene expression” refers to the expression of a gene’s code of information into proteins that manifest as the functional and structural entities of cells.

References:

1. Gatz M, Reynolds CA, Fratiglioni L, Johansson B, Mortimer JA, Berg S, Fiske A, Pedersen NL. Role of genes and environments for explaining Alzheimer disease. Archives of General Psychiatry. 2006 Feb; 63(2):168-74

2. Twamley EW, Ropacki SA, Bondi MW. Neuropsychological and neuroimaging changes in preclinical Alzheimer’s disease. J Int Neuropsychol Soc. 2006 September; 12(5): 707–735.

3. Strittmatter WJ, Saunders AM, Schmechel D, Pericak-Vance M, Enghild J, Salvesen GS, Roses AD. Apolipoprotein E: high-avidity binding to beta-amyloid and increased frequency of type 4 allele in late-onset familial Alzheimer disease.
Proc Natl Acad Sci U S A. 1993 Mar 1; 90(5):1977-81.

4. Corder EH, Saunders AM, Strittmatter WJ, Schmechel DE, Gaskell PC, Small GW, Roses AD, Haines JL, Pericak-Vance MA. Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer’s disease in late onset families. Science. 1993 Aug 13; 261(5123):921-3.

5. Cook KD, Myers AJ, Craig DW et al. A high-density whole-genome association study reveals that APOE is the major susceptibility gene for sporadic late-onset Alzheimer’s disease. J Clin Psychiatry. 2007 Apr;68(4):613-8

6. * Mutter J, Naumann J, Schneider R, Walach H. Mercury and Alzheimer’s disease
Fortschr Neurol Psychiatr. 2007 Sep;75(9):528-38. Epub 2007 Jul 12.

Weisgraber KH, Mahley RW. Human apolipoprotein E: the Alzheimer’s disease connection. FASEB J. 1996 Nov; 10(13):1485-94.

7. Kivipelto M, Rovio S, Ngandu T, Kåreholt I, Eskelinen M, Winblad B, Hachinski V, Cedazo-Minguez A, Soininen H, Tuomilehto J, Nissinen A. Apolipoprotein E epsilon4 Magnifies Lifestyle Risks for Dementia: A Population Based Study. Journal of Cellular and Molecular Medicine. 2008 Mar 4.

8. Kim N. Green, Lauren M. Billings, Benno Roozendaal, James L. McGaugh, and Frank M. LaFerla. Glucocorticoids Increase Amyloid-beta and Tau Pathology in a Mouse Model of Alzheimer’s Disease. The Journal of Neuroscience, August 30, 2006, 26(35):9047-9056

By Ralph Sanchez, L.Ac., CNS, D.Hom.

The two hallmark lesions that are associated with the damage that occurs in Alzheimer’s disease (AD) are neurofibrillary tangles and amyloid plaques (see pic 1). Processes involving inflammation, oxidative stress, * mitochondrial dysfunction, ** brain cholesterol dynamics (1) and others are tied into the formation of plaques and tangles. However, there has been a long-standing debate in the research community as to whether one lesion or the other is primarily responsible for the AD process.

Pic. 1

Neurofibrillary tangles are abnormally twisted fibers that form within nerve cells in the brain (neurons). The fibers are made up of a protein called tau, which is a key building block in the formation of the tubes that serve as an important conveyance network and structural support for the cell. The presence of these tubes that are called microtubules, aids the transfer of nutrients and brain chemicals that are vital to the relay of information between nerve cells (synapses) in the brain. In AD, the protein tau that forms the microtubule structure becomes “hyperphosphorylated”, *** which leads to the disruption of the microtubule’s biological function and it’s eventual collapse. (2) The loss of microtubules hinders communication between the neurons and the triggers the eventual death knell of the cell. Neurofibrillary tangles are also evident in other neurological diseases besides AD.

Amyloid plaques, also referred to as “senile plaques” or “Alzheimer’s plaques”, are clusters of fibers made of protein fragments called “beta-amyloid peptides” (BAP). In Alzheimer’s disease, these BAP fragments aggregate to form hard, insoluble plaques.
Numerous studies have argued that plaques play a role in the development of Alzheimer’s dementia and that amyloid plaques are primarily to blame for initiating the destruction of nerve cells in the brain. Plaque formation is associated with loss of neurons and their synapses, brain atrophy, and loss of brain tissue. What is not conclusive is how plaque contributes to the disease process of AD. Yes it “gums” up the brain and it’s workings, but what exactly happens in the cascade of events that causes the neuron to die? New evidence suggests that the memory loss and progressive degeneration characteristic of AD may develop even in the absence of amyloid plaques, and actually occurs before the hard plaque formation takes place. The mystery is slowly being untangled by science.

Alzheimer’s plaque formations were long thought to be the lesions accountable for the damage to the brain associated with AD and the subsequent cognitive deterioration that ensued. However, recent discoveries about beta amyloid (BAP) indicates that the damage to the neurons occurs by related processes, both outside and inside the nerve cell. In the early stage of plaque formation, BAP fragments form smaller aggregates (ADDLs) called “oligomers”. These BAP/oligomer clumps accumulate and attach in critical spaces between the neurons-synapses, which are vital connection and communication areas. The synapses between neurons, play an important role in the maintenance of proper memory and cognitive function. As the oligomers attach themselves to the synapses, cell communication is eventually blocked, leading to memory loss and the demise of the neuron. So we know more about what happens outside the neuron, yet there is more to it. What happens inside the neuron is another factor that is key to the Alzheimer’s puzzle.

While beta-amyloid (BAP) aggregation outside and between neurons creates the problems described above, beta-amyloid within the cell is now understood to be a central toxic factor that intiates microtubule instability and disruption of the nerve cell’s function.
Researchers at the University of Virginia recently found a connection between beta-amyloid and tau proteins that sheds some light onto the puzzle of what occurs in the AD process involving these two proteins. Research showed that when BAP comes in contact with cells that contain tau (not all neurons do), the beta amyloid proteins and tau combine and cause the break down of microtubules of the neuron (3). As microtubules are destroyed, nerve cells lose their ability to shuttle important maintenance and repair substances to the synapses, leading to a loss of connections between cells. The loss of nerve cell connections in Alzheimer’s patients leads to the death of nerve cells, memory loss, cognitive impairment, and dementia (4).

While the “tauists” and “BAPtists” have long made their case for tangles and amyloid plaque being most responsible for the decline associated with AD, a more enlightened understanding may be that these are not entirely separate processes. Beta amyloid oligomers forming in the synapses before they aggregate into hard insoluble plaques are seemingly responsible for initiating the destructive processes that lead to the death of neurons. By another mechanism, beta amyloid interactions with tau proteins within the neuron leads to microtubule instability with the eventual death of the neuron as well. Understanding these processes, can shed light onto solutions that may prevent or arrest Alzheimer’s in susceptible individuals. In coming articles I will delve into why these lesions begin to form and how we might prevent their occurrence.

The Alzheimer’s Solution multimedia ebook on how to prevent Alzheimer’s is coming soon . Sign up on my email list to be notified when the book is released.

God Bless! Ralph Sanchez, L.Ac.,CNS,D.Hom.

* Oxidative Stress: Relative imbalance of the body’s antioxidant defences to levels of “free radicals”. Free radicals are molecules that react easily with other molecules causing damage in the process. They are derived from normal metabolic processes and from environmental exposures. Antioxidants counter oxidative stress and protect the body from free radicals.

** Mitochondria: The mitochondria are the cells energy factories that power the body’s energy metabolism. Nutrient deficiencies, toxins and genetic influences can disrupt the optimum functioning of the mitochondria.
*** Hyperphosphorylated: Biochemical process that results in the conversion of tau protein in microtubules into tangles.

References:
1. Koudinova NV, Kontush A, Berezov TT, Koudinova A. (2003) Amyloid beta, neural lipids, cholesterol and Alzheimers’s disease. Neurobiology of Lipids, 1(6):27-33.

2. Bin Li, Muhammad Omar Chohan, Inge Grundke-Iqbal and Khalid Iqbal.(2006) Disruption of microtubule network by Alzheimer abnormally hyperphosphorylated tau. Acta Neuropathologica, Volume 113, Number 5 / May, 2007

3. King ME, Kan HM, Baas PW, Erisir A, Glabe CG, Bloom GS. (2006) Tau-dependent microtubule disassembly initiated by prefibrillar beta-amyloid. Journal of Cell Biology, 175(4):541-6.

4. LaFerla FM, Oddo S. (2005) Alzheimer’s disease: Abeta, tau and synaptic dysfunction.
Trends in Molecular Medicine. 11(4):170-6.