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14. Alzheimer Disease and the New Biology
- Johns Hopkins University Press
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14 Alzheimer Disease and the New Biology Larry Altstiel and Steven Paul Clinical research begins with the definition of a ‘‘case.’’ This generally starts as an empirical collection of clinical signs and symptoms that evolves over time into an accepted description of a distinct disease entity or syndrome. Clinical nosology is an iterative, almost evolutionary discipline that often leads to improved methods of diagnosis for a given disease entity. Equally important, it is a necessary prerequisite for unraveling the exact etiology and associated pathophysiology of the patient ’s illness, thus facilitating the ultimate goal of finding processes or mechanisms that are amenable to intervention. Alois Alzheimer’s description of the illness that now bears his name remains in use some ninety years after his pioneering descriptive studies (Alzheimer 1907). Alzheimer disease (AD) is a progressive, dementing illness that usually occurs in late life but with variable age of onset. Approximately 4 percent of persons over the age of 65 have AD, and by age 85 the prevalence may range from 25 to 45 percent (Breitner et al. 1988; Evans et al. 1989). The incidence of the disease doubles approximately every five years after age 65 (Beard et al. 1995). Current AD therapy is directed toward symptomatic treatment of cognitive deficits and appears to have little effect on either disease incidence or progression. Given the emergence of AD as a critical public health problem in an ever-aging population, development of agents that may slow the disease’s progression or reduce its incidence is of paramount importance. 262 Larry Altstiel and Steven Paul As initially noted by Alzheimer, the brains of AD patients are remarkable for generalized atrophy, numerous plaques (senile plaques) that have an amyloid core surrounded by dystrophic neurites, cerebrovascular amyloid, and neurofibrillary tangles (Alzheimer 1907; Glenner 1989). The amyloid deposits are formed from a 40–42 amino acid peptide (Ab), which is in turn derived from a larger precursor protein, the b-amyloid precursor protein (APP) (Kang et al. 1987). Compelling evidence has implicated Ab deposition as a principal factor in AD pathology . Rare families have been found in which mutations in the APP gene results in an autosomal-dominant form of early onset AD. These mutations in APP flank the amino acids, which must be cleaved in order to produce Ab, the primary constituent of the plaque (Selkoe 1996). Mutations in the presenilin genes (PS-1, PS-2) have been identified and appear to be responsible for additional forms of early-onset autosomaldominant AD (Van Broeckhoven 1995). The mutated forms of PS-1 and PS-2 appear to alter processing of APP in a manner that leads to accumulation of the more amyloidogenic forms of Ab (Borchelt et al. 1997). While the role of Ab as a direct cause of AD has not been unequivocally established, there is compelling evidence that Ab accumulation may both be directly neurotoxic and promote chronic neurodegeneration (Selkoe 1996). Moreover, patients with Down syndrome, who have an extra copy of chromosome 21 (the location of the APP gene), almost invariably develop AD pathology (Mann et al. 1986). Taken together, these findings from both patients with early-onset AD and patients with Down syndrome suggest that aberrant Ab deposition is an important early event in the pathogenesis of AD. While the exact mechanisms of Ab synthesis and APP processing are not completely understood, it is generally assumed that the proteolytic processing of APP occurs via a series of proteases that cleave the precursor protein in discrete regions. The g secretase, for example , cleaves APP at the C-terminal end of the Ab sequence, whereas the b-secretase cleaves proximal to the N-terminus. Importantly, an a-secretase cuts within the Ab sequence itself and leads to production of a soluble form of APP (APPs) and a nonamyloidogenic fragment of APP (Selkoe 1996; Lendon, Ashall, and Goate 1997). Thus, drugs that inhibit the g or b secretases, or stimulate a-secretase, could reduce Ab production and thereby alter (perhaps slow) the progression of AD. The identification of specific gene mutations that cause AD has prompted the recent development of animal models that have relevant AD pathology. These models have greatly accelerated the pace of research in APP processing and deposition. One such model, developed by [18.208.203.36] Project MUSE (2024-03-19 11:24 GMT) Alzheimer Disease and the New Biology 263 Eli Lilly and Company and Athena Neurosciences, is a transgenic mouse that overexpresses a...