FIGURE 4 PS1 A246E FAD mutant transgene greatly accelerates amyloid plaque pathology of Tg2576 transgenic mice. Brain sections of the hippocampus of transgenic mice co-expressing APP K670N/M671L (the Tg 2576 line) and PS1 A246E FAD mutant transgenes were immunostained with Ap specific mAb 6E10 and compared to that of age-matched Tg2576 transgenic animals. Panels are hippocampi of mice 7, 9, and 13 months of age. At all ages examined, both the density and the size of plaques in heterozygous doubly transgenic mice far exceeded that of heterozygous APP mice at comparable ages. Consistent plaque deposits were detected in 7-month-old heterozygous doubly transgenic mice when the APP transgenic mice were free of plaques. At 9 months of age, while APP transgenic mice exhibit occasional diffuse Ap plaques, doubly transgenic mice showed numerous Ap deposits in various regions of the brain, including cerebral cortex (data not shown) and hippocampus. Ap load was further enhanced in 13-month-old doubly transgenic mice, and multiple brain areas were covered with plaques. Wild-type human PS1 transgene does not accelerate plaque deposition when co-expressed with the mutant APP transgene (data not shown). Littermates that express PS1 A246E alone do not develop detectable amyloid plaques up to 14 months of age (data not shown). Data courtesy of Dineley et al. (74).

3. The genetics of AD also support the hypothesis. Familial AD (FAD) is associated with the inheritance of specific genes, be they mutated genes or the presence of specific allele types. All known FAD gene products directly or indirectly impinge upon Ap peptide production, resulting in increased Ap levels in the CNS—we will return to this in more detail in the next section (see Box 3 as well).

If Ap causes AD, how does this happen? The basic mechanisms underlying Ap-mediated neuronal dysfunction and neuronal loss are unknown and, of course, a topic of much vigorous investigation. A number of scenarios are in play at present. A variety of evidence suggests the involvement of senile plaque components in triggering inflammatory responses that culminate in neuronal death. Plaque structures appear to act as irritants and initiate inflammatory responses. For example, hypertrophic astrocytes and activated microglia often surround plaques (47), and these responses likely lead to localized cell death. The overproduction of reactive oxygen species by inflammatory process or even direct chemical catalysis by the Ap peptide, with resulting oxidative toxicity, is another hypothesis. A large number of research groups are working in the general area of testing for effects of Ap as causing altered activation of cellular signaling processes such as protein kinases and phosphatases. The idea is that derangement of these signaling cascades can lead to both derangements of synaptic physiology and altered phosphorylation of proteins such as tau, that are known to be associated with cell death. Another idea is that Ap peptide binds to cell-surface receptors in order to trigger its deleterious effects. My laboratory and a number of others are currently working on the idea that neuronal nicotinic acetylcholine receptors are targets of Ap peptide (see Box 2). Misregulation of these surface ion channels could lead to both synaptic and cellular derangement; additionally, this mechanism could provide an explanation for the selective loss of cholinergic fibers and their targets in AD.

Even though the processes that Ap peptide triggers still remain mysterious, a parsimonious explanation consistent with most of the available data is the idea that amyloid beta peptide causes AD. In the next section, we will review some of the strongest evidence available supporting this idea—findings that gene mutations known to invariably cause AD in humans occur in genes directly linked to the production of amyloid beta peptide.

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