title: [Alzheimer disease: cellular and molecular aspects].
abstract: A conclusive diagnosis of Alzheimer's disease (AD) can be made only by correlating clinical findings and neuropathological studies of post-mortem tissues. Two leading neuropathological changes correlate with the diagnosis of AD: first, the neurofibrillary tangles (NFTs) which accumulate in neuronal perikarya and are made of paired helical filaments (PHFs) containing the microtubule-associated protein tau; second, extracellular amyloid deposits in the form of diffuse or neuritic senile plaques which contain the amyloid peptide. In AD, NFTs can be easily visualized using antibodies recognizing the microtubule associated protein tau and are composed of bundles of PHFs. In the autopsy-derived AD brain, tau is hyperphosphorylated and more than 30 phosphorylation sites have been identified in PHF-tau proteins. The formation of NFTs is thought to be associated with a collapse of the microtubule network, disturbances of axoplasmic transports, synapse loss, neuritic atrophy, and neuronal death. Senile plaques are extracellular lesions which have been shown by electron micro-scopic studies to contain amyloid fibrils. Fibrils were isolated and a small 4.2 kDa poly-peptide was purified from this material. The amyloid peptide found in amyloid deposits of AD is designated Abeta. Since the Abeta peptide is small and unlikely to be a primary translational product, it was predicted to arise from a larger precursor. In 1987, this amyloid peptide precursor (APP) was characterised from the analysis of a full-length cDNA encoding a primary translational product of 695 residues. This protein is synthetized by neurons as a 100-kDa glycosylated transmembrane protein with a single membrane spanning domain. The use of cellular models has clearly identified two catabolic pathways for APP. A non amyloidogenic pathway, in which APP is cleaved by beta-secretase within the sequence of the amyloid peptide. This cleavage precludes the formation of the full-length Abeta found in the amyloid core of senile plaques. A second catabolic pathway of APP leads to the production of Abeta from its precursor. In this amyloidogenic pathway, APP is cleaved by beta-secretase at the N-terminus of Abeta. The C-terminal fragment of APP thus formed is in turn cleaved by beta-secretase to release the full-length amyloid peptide. In primary cultures of neurons over-expressing APP, the production of intraneuronal Abeta induces neuronal apoptosis. This neurotoxicity, which is not observed in epithelial cells, seems to be related to the formation of intraneuronal aggregates of Abeta 1-42. In AD, the specific inhibition of beta- or beta-secretase activities would decrease the production of Abeta from its precursor, in such a way that its relative concentration could be low enough to avoid the formation of aggregates. Molecules which can interact with Abeta in order to inhibit its aggregation are also being developed. Immunization against Abeta has also been tested in both animal models and clinical studies. Although these clinical studies had to be interrupted due to the development of T-lymphocyte meningoencephalitis in some patients, very preliminary results indicate that antibodies against Abeta slow cognitive decline in AD, and generate areas of neocortex devoid of senile plaques.
authors.forename: J N
authors.initials: JN
authors.lastname: Octave
mesh_terms: D000544:Alzheimer Disease / Q000175:diagnosis / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D001530:Belgium; D001921:Brain / Q000378:metabolism / Q000473:pathology; D002800:Cholinesterase Inhibitors / Q000627:therapeutic use; D004195:Disease Models, Animal; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D016874:Neurofibrillary Tangles / Q000473:pathology; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D058225:Plaque, Amyloid / Q000473:pathology; D016875:tau Proteins / Q000378:metabolism
chemical_list: D016564:Amyloid beta-Protein Precursor; D002800:Cholinesterase Inhibitors; D016875:tau Proteins