[HTML][HTML] Deciphering the genesis and fate of amyloid β-protein yields novel therapies for Alzheimer disease

DJ Selkoe - The Journal of clinical investigation, 2002 - Am Soc Clin Investig
The Journal of clinical investigation, 2002Am Soc Clin Investig
Nonstandard abbreviations used: Alzheimer disease (AD); amyloid β-protein (Aβ); amyloid β-
protein precursor (APP); transmembrane (TM); amyloid β-protein precursor intracellular
domain (AICD); presenilin (PS); notch intracellular domain (NICD); insulin-degrading
enzyme (IDE); cerebrospinal fluid (CSF); long-term potentiation (LTP). of Aβ) plus the APP
intracellular domain (AICD). The latter has proved exceedingly difficult to detect but was
recently localized to both cytoplasm and nucleus (7–9). Alternatively, other APP holoproteins …
Nonstandard abbreviations used: Alzheimer disease (AD); amyloid β-protein (Aβ); amyloid β-protein precursor (APP); transmembrane (TM); amyloid β-protein precursor intracellular domain (AICD); presenilin (PS); notch intracellular domain (NICD); insulin-degrading enzyme (IDE); cerebrospinal fluid (CSF); long-term potentiation (LTP). of Aβ) plus the APP intracellular domain (AICD). The latter has proved exceedingly difficult to detect but was recently localized to both cytoplasm and nucleus (7–9). Alternatively, other APP holoproteins can be cleaved 16 residues N-terminal to the α-secretase site by a novel membrane-anchored aspartyl protease called β-secretase (or BACE1)(reviewed in ref. 10). This scission creates C99, which is similarly processed by γ-secretase to yield Aβ and AICD. Precisely where in the cell the βand γ-secretases cleave APP is unsettled. Considerable evidence favors recycling endosomes, but the trans-Golgi network and secretory vesicles and perhaps even earlier secretory compartments (the endoplasmic reticulum and the cis-Golgi stacks) represent additional candidates (see, for example, ref. 11). It should be borne in mind that the APP-processing events just summarized are entirely normal and occur to varying degrees in virtually all neural and non-neural cells throughout the body. Certain genetic defects that cause autosomal dominant AD, such as mutations in APP or the presenilin (PS) genes PS1 and PS2, augment the amyloidogenic pathway of APP processing in all cells in a way that favors production of the highly self-aggregating Aβ1-42 variant over the slightly shorter and less hydrophobic Aβ1-40 form. Aβ1-42 normally comprises only about 5–10% of total secreted Aβ peptides, but this fraction rises to about 15–40% when either APP or PS is mutant.
The Journal of Clinical Investigation