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Abstract
The major component of Alzheimer's disease amyloid is the 4 kDa peptide βA4 which is produced from an integral membrane protein (amyloid beta precursor protein, AβPP) by proteolytic processing. Cleavage of the βA4 domain from the precursor protein is part of a complex process which results in the release of AβPP from the membrane. AβPP is released by cleavage within the βA4 domain by a putative a-secretase. However, other cleavage sites exist, one of them being located at the NH2-terminus of βA4. Several factors such as genetic mutations within or near the βA4 domain, inappropriate production of AβPP isoforms, increased AβPP synthesis, or alterations in AβPP trafficking seem to favor this “amyloidogenic” cleavage, which is due to β-secretase activity. A major determining event in the production of βA4 amyloidogenic species appears to be the COOH-terminal cleavage, due to γ-secretase activity. This generates species either of 39/40 residues or longer species of 42/43/44 residues which have a greater tendency to aggregate. A central focus of current research is to elucidate the cellular trafficking and targeting of AβPP in order to understand how the various proteolytic systems operate and are selected. This could lead to the development of therapeutic agents which control the formation, aggregation or mobilization of cerebral amyloid in Alzheimer's disease.