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''Alzheimer's disease (AD) is a devastating illness that robs humans of their ability to remember, to think and to understand all the things we cherish most about being human.'' (P.F. Chapman)

Alzheimer's disease (AD) is an epidemic neurodegenerative disorder claiming millions of victims per year. The aging of the world population will be accompanied by an even higher toll. According to the World Health Organization the prevalence of Alzheimer's disease is 5.5% above 60 years of age and increases for elderly people (clinical AD: 16% 85 years, 22% 90 years) [1, 2]. ''The onset of Alzheimer's disease is usually after 65 years of age, though earlier onset is not uncommon. As age advances, the incidence increases rapidly (it roughly doubles every 5 years).'' Thus age is the dominant risk factor overruling even the positive impacts of nutrition and education. The socio-economic impact of Alzheimer's disease, the care needed for disabled and chronically wasting patients, the consequences for patients, relatives, and caretakers alike will be a major social and financial issue for the coming decades. ''The direct and total costs of this disorder in the United States have been estimated to be US$536 million and US$1.75 billion, respectively, for the year 2000.''

The exact cause of Alzheimer's disease remains unknown, although a number of factors have been suggested. These include metabolism and regulation of amyloid precursor protein, plaque-related proteins, tau proteins, zinc, copper, and aluminum [1].

Improvements in medication by use of acetyl cholinesterase inhibitors and general therapy significantly reduce symptoms at the onset of the disease [3, 4] but do not address the severe mortality in the final stages. A causal therapy is, therefore, still very much in demand, because no existing therapy effectively stops or even cures the disease. Identification of gene mutations linked to Alzheimer's disease-afflicted families in London and Sweden and additional polymorphisms that either cause or promote Alzheimer's disease have provided some insight into the biological pathways and the involvement of the amyloid precursor protein (APP) [5-8].

Processing of APP by Secretases

C83 APP CS9 Scheme 3.5.1. Amyloid precursor protein (APP) degradation. a = a-secretase, b = b-secretase, g = g-secretase, C83 = 83 C-terminal amino acid, C99 = 99 C-terminal amino acids.

A simplified diagram of amyloid precursor protein (APP) processing is depicted in Scheme 3.5.1. The up to 771 amino acid long APP, which occurs in three iso-forms: APP695, APP751, and APP771, includes a signaling sequence, a large extra-membranous sequence, and the crucial membrane-spanning domain, which is followed by a short cytoplasmic tail. Non-pathological cleavage occurs between Lys687 and Leu688 (K16L17 in Scheme 3.5.2) under the action of a-secretase (also called TACE) producing a-APP and ultimately the fragments p3 and C83. a-Secretase belongs to the ADAM family and is sensitive to membrane cholesterol levels and can thus be modulated by cholesterol-reducing diets or drugs [9]. The most relevant point mutations for Ab formation are K670 M671 ! NL and V717 ! Phe (Stockholm or Indiana), which cause familial Alzheimer's dementia (FAD). The molecular consequence of these point mutations is a different modulation of the three secretases, which act in concert to degrade APP. Usually 90% of APP is degraded by the a-secretase pathway, and despite years of intense research, the purpose of this degradation is still obscure. Rate-limiting b-secretase usually cleaves just 10% of all APP between the Met671-Asp672 residues, but prefers the preceding amino acids Asn670Leu671 of the Swedish mutation over Lys670Met671. The V717 ! Phe mutation results in enhanced cleavage after Ala714, leading to the notorious Ab42.

The genetic background of Alzheimer's disease is quite heterogeneous, and many associations have been made with locations on almost every other chromosome. Replicated or confirmed associations are, however, few. Late-onset Alzheimer's disease is linked to the e4-allele of ApoE (which is the 4th identified functional mutation of an important transporter protein coded by multiple genes on different chromosomes). Mouse models expressing mutated human APP and presenilin 1 display many symptoms of Alzheimer's disease, although no model represents the full range of pathologies of the human disease. In particular the inflammation processes in humans and mice do not adequately relate to each

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