Alzheimer disease (AD) is a progressive degenerative disease of the brain that is characterized by neocortical atrophy, neuron and synapse loss, and the presence of extracellular senile plaques and intracellular neurofibrillary tangles (NFTs). The primary clinical manifestation of AD is a profound global dementia that is marked by severe amnesia with additional deficits in language, “executive” functions, attention, and visiospatial and constructional abilities. The neurodegenerative changes occur primarily in the hippocampus and entorhinal cortex and in the association cortices of the frontal, temporal, and parietal lobes. Although the temporal progression of the neuropathological changes of AD is not fully known, recent studies suggest that the hippocampus and entorhinal cortex are involved in the earliest stage of the disease, and that frontal, temporal, and parietal association cortices develop pathology as the disease progresses. This “spreading” of the pathology from those regions of the brain in which hallmarks of the disease (amyloid plaques, reactive gliosis, NFTs) can be first detected, to other regions of the brain is notable, and while generally accepted as being a genuine feature of the pathology, no explanation for it has yet emerged (1). As the population ages, the projected number of individuals that will be affected by dementia, and AD in particular, indicates that a serious public health problem is looming. However, intense research over the past decade has begun to uncover some of the cell and molecular processes leading to neuronal loss with the discovery of possible targets for therapeutic intervention, raising the hope that we may be able at least to halt the progression of the disease (2, 3). The major constituent of senile plaques is the β-amyloid peptide, which is derived from the amyloid precursor protein (APP) by proteolytic cleavage (3). This peptide is invariably described as a 40– to 42–amino acid peptide, although numerous shorter x-40 and x-42 forms are found, particularly in the AD brain, and many of these peptides have a strong tendency to aggregate (4). By contrast, the intracellular NFTs are fibrillar aggregates of the microtubule-associated protein tau (5). The vast majority of AD cases are “spontaneous,” in that there is no familial history of the disease and hence no known genetic linkage that predisposes an individual to develop AD. However, the rare cases of familial AD have proven to be key in the identification of three genes, APP and presenilins 1 and 2 (PS1 and PS2), that, when mutated, lead to early-onset familial forms of the disease (6). Each of these gene products plays a role in the production of β-amyloid peptides; APP is the precursor protein from which β-amyloid peptides are derived by proteolytic cleavage at the β and γ cleavage sites (Figure (Figure1a).1a). Familial mutations in APP and both presenilins increase the plasma levels of β-amyloid in patients carrying these mutations and tip the balance toward an increase in the production of x-42, the more fibrillogenic species (7, 8). Mutations in APP close to the β and γ cleavage sites (Figure (Figure1b)1b) accelerate amyloid production and increase the proportion of the amyloidogenic Aβ x-42 species (3). Presenilin mutations appear to directly affect cleavage site selection and the frequency of cleavage at the γ-site, and PS1 is absolutely required for γ-cleavage of APP (3). Early biochemical characterization and inhibitor profiling indicated that both β and γ cleaving enzymes (secretases) were probably aspartic proteinases and hence represented attractive therapeutic targets (9). Figure 1 APP processing pathway and and domain organization of β-secretase. (a) A schematic representation of the sequential cleavages of APP at the β- and γ- sites to generate β-amyloid. APP and β-secretase are both integral ...
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May 6, 2004
Antonio Orlacchio + 7
Open Access