The Amyloid Connection

Amyloid degeneration and amyloidoses have been discussed briefly in Chapter 6. The term "amyloid" given to these deposits over 100 years ago implies erroneously that they are formed of a starch-like substance (Latin amylum for starch). Actually, the amyloid molecules are normal or mutated proteins or protein fragments that differ among the various amyloidoses they generate (Chapter 6).

As previously stated, in the brain, amyloid b (Ab ) peptide, the major component of the neuritic plaque amyloid, is thought to be the pathogenic molecule in AD. What causes its significant accumulation in AD is not yet clearly known. The Ab peptide, which contains 40 to 42 amino acids, derives from a larger molecule, the amyloid precursor protein (APP), a transmembrane molecule with 695 amino acids, which normally undergoes cleavage at multiple sites. APP itself does not harm the cells; it is only when Ab peptide is clipped out of APP by protein-splitting enzymes (secretases) that the smaller molecule may lead to pathology (108). APP is embedded in the cell membrane vesicles (endosomes), while the Ab molecule sits astride the membrane, where it cannot be reached by the proteinsplitting enzymes (109).

During normal cellular processing, APP is split by the enzymes a-secretase, b-secretase, and g-secretase. Processing of a-secretase occurs at or near the cell surface and, in AD, an underactivity of this enzyme precedes the formation of Ab. Overactivity of the b-secretase may yield fragments that contain Ab, which give rise to amyloid degeneration and accumulation (Chapter 6). This reaction occurs in the Golgi apparatus and lysosomes, the cell organelles that are usually the site of protein breakdown (109). Overactivity of the third proteolytic enzyme, g-secretase, can also cause overactivity of the Ab peptide. This occurs at the carboxyterminal segment. The question as to the identity of the factor(s) capable of causing this over- or underactivity of the secretases remains unanswered, but genetic mutations in the proteins, presenilin I and II are thought to be involved. Other theories regarding the role of the Ab protein include

■ alterations occurring during the early secretory trafficking of APP in the endoplasmic reticulum and Golgi apparatus or in endocytic recycling,

■ presence of an APP mutation, or

■ alterations in protein phosphorylation, and

■ abnormalities of lysosomes (i.e., cell organelles containing hydrolytic enzymes involved in degradation of foreign materials engulfed by phagocytes).

Once Ab-peptide has aggregated inside the lysosome, the cell has difficulty getting rid of it. Ab-peptide accumulation would lead to cell damage and death; this is followed by amyloid accumulation in the extracellular spaces and formation of the neuritic plaque (with the remnants of the neurofibrillary tangles from the dead cell and other debris). At this point, microglial cells from the immune system would surround the plaque (Chapter 6, Figure 10). Some investigators emphasize that brain damage starts with the formation of amyloid by perivascular macrophages and microglial cells (110). The damage and loss of neurons would cause a selective loss of neurotransmitters, with alterations in synaptic signaling. The presence of an inflammatory component in the formation and accumulation of the neuritic plaques and amyloid deposits (110,111) provided the rationale for using anti-inflammatory drugs to prevent and treat and for attempts—thus far unsuccessful—to prepare a vaccine against the disease (126,127).

Ab peptide or APP cleavage products are neurotoxic. The major factors held responsible for this toxicity include n disruption of Ca2+ homeostasis by membrane damage and, thus, increased neuronal intracellular Ca2+, n the increased intracellular Ca2+, which would be responsible for the tau protein hyperphosphorylation and the formation of PHFs, which, in turn, form neurofibrillary tangles, n the cascade of events leading to NFTs, which may be induced by elevated levels of Ab (128).

Not all investigators support a central pathogenic role for Ab protein in AD; their reluctance to accept the amyloid connection as the primary cause of AD is due, in part, to the lack of definitive evidence for a specific neurotoxic species of Ab and of its effects on synaptic function in vivo. Rather, soluble oligomers (i.e., polymers consisting of a small number of units) formed within intracellular vesicles and, subsequently, secreted by the cells, would be responsible for the disruption of synaptic plasticity in AD. Moreover, prevention of the oligomer formation and cytotoxicity would restore synaptic plasticity (128-130).

Other studies support a normal (physiologic) rather than a pathologic role for Ab; accordingly, symptoms of dementia may occur before significant plaque buildup and cell loss are evident. Other studies suggest a beneficial function of Ab on the synapse. Thus, AD would be caused by synaptic failure rather than by neuronal death: neuronal activity would induce formation of Ab and, in turn, the secreted Ab would depress neuronal activity by a negative feedback function and reestablish synaptic balance, contribute to neuronal health, and regulate neuronal activity (130-133).

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How to Stay Young

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