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 28,634 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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.
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PMID:[Alzheimer disease: cellular and molecular aspects]. 1676 48

Converging lines of evidence on the possible connection between NGF signaling and Alzheimer's diseases (AD) are unraveling new facets which could depict this neurotrophin (NTF) in a more central role. AD animal models have provided evidence that a shortage of NGF supply may induce an AD-like syndrome. In vitro experiments, moreover, are delineating a possible temporal and causal link between APP amiloydogenic processing and altered post-translational tau modifications. After NGF signaling interruption, the pivotal upstream players of the amyloid cascade (APP, beta-secretase, and active form of gamma-secretase) are up-regulated, leading to an increased production of amyloid beta peptide (Abeta) and to its intracellular aggregation in molecular species of different sizes. Contextually, the Abeta released pool generates an autocrine toxic loop in the same healthy neurons. At the same time tau protein undergoes anomalous, GSKbeta-mediated, phosphorylation at specific pathogenetic sites (Ser262 and Thr 231), caspase(s) and calpain- I- mediated truncation, detachment from microtubules with consequent cytoskeleton collapse and axonal transport impairment. All these events are inhibited when the amyloidogenic processing is reduced by beta and gamma secretase inhibitors or anti-Abeta antibodies and appear to be causally correlated to TrkA, p75CTF, Abeta, and PS1 molecular association in an Abeta-mediated fashion. In this scenario, the so-called trophic action exerted by NGF (and possibly also by other neurotrophins) in these targets neurons is actually the result of an anti-amyloidogenic activity.
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PMID:Nerve growth factor as a paradigm of neurotrophins related to Alzheimer's disease. 2018 3