Taken together, the direct cleavage of APLP1 is a novel feature of the γ-secretase prompting a re-thinking of γ-secretase activity modulation as a therapeutic strategy for Alzheimer disease.
In conclusion, our results establish that APLPs show typical features of SAMs and indicate that increased surface expression, as observed for APLP1, is essential for proper synapse formation <i>in vitro</i> and synapse maintenance <i>in vivo</i><b>SIGNIFICANCE STATEMENT</b> According to the amyloid-cascade hypothesis, Alzheimer's disease is caused by the accumulation of Aβ peptides derived from sequential cleavage of the amyloid precursor protein (APP) by β-site APP cleaving enzyme 1 (BACE1) and γ-secretase.
Consistently, knockdown or antagonization of DOR reduces secretase activities and ameliorates Abeta pathology and Abeta-dependent behavioral deficits, but does not affect the processing of Notch, N-cadherin or APLP in AD model mice.
The amyloid precursor-like protein-1 (APLP1) is a member of a protein family that includes the Alzheimer's disease-associated amyloid precursor protein (APP).
Presence of a "CAGA box" in the APP gene unique to amyloid plaque-forming species and absent in all APLP-1/2 genes: implications in Alzheimer's disease.
Our results suggest that even though APLP1 and APLP2 cannot generate Abeta, they may potentially contribute to the pathology of AD by generating peptide fragments whose toxicity is comparable to that of APPC31.
Amyloid-precursor-like protein 1 (APLP1) is a membrane-associated glycoprotein, whose gene is homologous to the APP gene, which has been shown to be involved in the pathogenesis of Alzheimer's disease.