paired helical filaments and be responsible for the loss of cholinergic neurons in certain brain areas (117). Mutation in the prion protein may, in humans, lead to inherited familial "transmissible spongiform encephalopathies," such as the Creutzfeldt-Jakob's disease, with abnormal protein aggregates and dementia. The possible role of prions in AD etiopathology has called attention to the possibility that disorders of immune responses may cause or contribute to AD pathology (Chapter 14). The presence of abnormal brain proteins, their intra- and extracellular accumulation, and the resulting inflammation and proliferation of microglia, the immune cells of the brain, may activate immune responses that would further aggravate neural damage (118).

Still uncertain at present is whether AD lesions originate in the neurons and then spread to the extracellular and perivas-cular spaces or whether they are blood borne and are carried to the brain through a damaged blood-brain barrier. Most researchers in the field consider the amyloid-b fragment of the amyloid precursor protein (APP) to be the pathogenic molecule in AD (117). Nerve cell injury is viewed by others as the primary cause, and extracellular lesions, such as deposition of amyloid fibrils, are viewed as the secondary cause. Intracellular lesions may be consequent to or associated with alterations of cytoskeletal protein phosphorylation by protein kinases and accumulation of brain proteases or of toxic metals such as iron (118), zinc (119) and aluminum (120,121).

Biochemical analysis of perihelical filaments (PHFs) that accumulate intracellularly to form neurofibrillary tangles demonstrates that the principal PHF protein subunit is an altered form of the microtubule-associated tau protein (122125). Tau protein is known to bind to tubulin and promote the assembly and stability of microtubules. With aging, tau proteins may become hype-phosphorylated (identified as A68 proteins and detected by the specific Alz 50 antibody) (124), perhaps due to increased activity of several kinases. As a consequence, these proteins would no longer be capable of stabilizing the micro-tubules, and, thus, PHFs and neurofibrillary tangles would form (108). By far the most popular but still controversial theory of AD pathogenesis today involves the overproduction of amyloid bprotein. The following is a synopsis of the major steps in the so-called "amyloid connection."

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