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.

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.

APP to Beta-Amyloid Plaque_NIA

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.

* 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.

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.


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