Molecular Causes of the Disease

For over a hundred years neuroscientists have debated whether the accumulation of lipofuscin (age pigments) in neurons is a cause of dementia. It has been argued that lipofuscin is formed by lipid peroxidation, but this seems unlikely insofar as these pigments are primarily composed of protein and carbohydrate. Recent evidence has shown that glycation (protein cross-linking by sugar) is probably a greater cause of lipofuscin formation than lipid peroxidation. Although a role for lipofuscin cannot definitely be ruled out, few neurologists today believe that it is a central factor in Alzheimer’s disease.

*Caution: This section is highly technical. It is written for the benefit of the physician, or knowledgeable lay person. It is not necessary that you understand this section to benefit from the treatment protocols that have been suggested.

In the 1970s many neurologists became convinced that Alzheimer’s disease is due to degeneration of the basal forebrain neurons which send the neurotransmitter acetylcholine to the cerebral cortex. There are less than half-a-million acetylcholine-producing neurons in the basal forebrain nuclei, but these neurons specifically innervate areas of the cerebral cortex that play a key role in memory formation — the hippocampus, in particular. Most neurologists now believe, however, that degeneration of cholinergic neurons in Alzheimer’s disease is only one manifestation of widespread degeneration of cognitively important neurons in the cerebral cortex and associated areas of the brain.

The most characteristic features of Alzheimer’s disease are senile plaques of beta-amyloid peptide, neurofibrillary tangles, loss of synapses, and (ultimately) death of neurons. Although neurofibrillary tangles are more closely associated with neuron death than beta-amyloid, the evidence is becoming convincing that beta-amyloid is the factor most responsible for starting the degenerative processes of Alzheimer’s disease.

Both neurofibrillary tangles and beta-amyloid senile plaques are due to protein abnormalities. The beta-amyloid peptide present in the core of senile plaques is a 42 amino-acid chain produced by cleavage of a larger protein known as amyloid precursor protein (APP). APP is normally found embedded in neural membranes, and is thought to contribute to stabilizing contact points between synapses. Beta-amyloid resists the degradation enzymes that normally recycle cellular proteins. Aggregates of beta-amyloid accumulate throughout brain tissue in normal aging, but do not cause pathology as long as the aggregates are diffused throughout the cell. The damage begins when the beta-amyloid becomes concentrated in senile plaques.

Neurons, and in particular the axons of neurons, use microtubules to transport substances between the center of the neuron and its outer portions. The assembly and structural integrity of microtubules is dependent upon several proteins, the most important of which is a protein called “tau”. When tau is abnormally phosphorylated, it forms the paired helical filaments known as neurofibrillary tangles. Why this abnormal phosphorylation occurs is unknown, but the loss of microtubule transport is particularly damaging in neurons that produce and release large amounts of neurotransmitter. The large pyramidal neurons of the cortex and the forebrain acetylcholine neurons (among others) that are important for cognition have more microtubules than other neurons — and these large neurons have the most neurofibrillary tangles in Alzheimer’s disease.

Genetic mutations account for less than 5% of Alzheimer’s Disease patients, but these genetic abnormalities have contributed significantly to understanding what causes the disease. The first gene linked to inherited Alzheimer’s was the APP gene on chromosome 21. (Down’s syndrome victims, who invariably develop Alzheimer’s if they live beyond 40, have three copies of chromosome 21.) Most other genes associated with Alzheimer’s are either linked to beta-amyloid production or are of unknown function. But the gene on chromosome 17 that encodes tau polypeptides is not associated with inherited forms of the disease.

The second gene discovered to be responsible for an inherited form of Alzheimer’s disease was the gene on chromosome 19 responsible for cholesterol transport protein: apolipoprotein-E (apoE). People with the ApoE4 gene on both copies of chromosome 19 are eight times more likely to develop Alzheimer’s than people with two copies of ApoE2 or ApoE3. Beta-amyloid binds most readily to ApoE4. ApoE4 facilitates the transformation of beta-amyloid from the diffuse form to the aggregated form.

Free radical damage is probably the most significant cause of biological aging. The second most significant cause of aging is probably the nonenzymatic cross-linking of proteins by sugars — a process known as glycation. The body protects itself from glycation by periodic degradation and replenishment of proteins. But long-lived proteins like collagen are particularly vulnerable to glycation, which is why our tissues become more fibrous and less resilient as we age.

Insoluble proteins like aggregated beta-amyloid and phosphorylated tau are especially liable to form advanced glycation end-products (AGEs). The cross-linking further increases insolubility and also leads to protein-binding of metals such as iron and copper, which generates toxic hydroxyl free radicals. Glycated proteins produce nearly 50 times more free radicals than nonglycated proteins. Lipid peroxidation caused by beta-amyloid results in an aldehyde called 4-hydroxynonenal that binds to proteins involved in transport of ions and binds to proteins that transport glucose. With impaired ion and glucose transport, neurons begin to degenerate.

Beta-amyloid can also bind to complement protein C1, thereby leading to an immune-inflammatory response. The resulting cytokines are thought to trigger more beta-amyloid cleavage from APP. When beta-amyloid is added to cultured neurons or injected into the cerebral cortex of nonhuman primates, it leads to the appearance of the phosphorylated tau-protein of neurofibrillary tangles.

To summarize the current hypothesis: It appears that Alzheimer’s disease begins with gradual accumulation of beta-amyloid peptide in the form of diffuse plaques which, through glycation and oxidation evolve into senile plaques. Certain neurons with high metabolic demands or special sensitivity to beta-amyloid develop neurofibrillary tangles which are even more destructive than beta-amyloid deposits. These neurons may include those in nuclei outside of the cerebral cortex which activate the cortex with modulatory neurotransmitters such as acetylcholine, serotonin and noradrenaline. Such nuclei are normally nurtured by nerve growth factor (NGF) traveling down the axons, but the NGF may be replaced by beta-amyloid, which leads to neurofibrillary tangles. Degenerating neurons activate the immune/inflammatory system which activate cytokines, such as interleukin-1 and interleukin-6. Interleukin-1 increases the toxicity and interleukin-6 increases the production of beta-amyloid. A vicious cycle of inflammation and beta-amyloid production — along with glycation and oxidation of tau-protein and beta-amyloid — ultimately results in the destruction of large numbers of brain cells.

Source: Life Extension Foundation 1998-1999

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