Cognitive deficits are ameliorated by reduction in amyloid β accumulation in Tg2576/p75(NTR+/-) mice.

Abstract Aims Amyloid β (Aβ) is considered to be an important mediator of the development and progression of Alzheimer's disease (AD). Its direct binding to p75 NTR , not TrkA, induces apoptosis, which is thought to be the most relevant feature of p75 NTR regarding AD. In the present study we explored the regulation of p75 NTR on Aβ production and accumulation during AD pathology. Materials and methods We generated Tg2576/p75 NTR +/− mice by crossing the transgenic AD mice (Tg2576) with p75 NTR −/− mice to lower the p75 NTR level. Under these conditions, we evaluated cognitive function using the Morris water maze, pathology and process by which two types of Aβ (Aβ40 and Aβ42) are produced, by enzyme-linked immunosorbent assay and Western blotting. Key finding The results showed that cognitive deficits were rescued in Tg2576/p75 NTR +/− mice compared with those in Tg2576 mice. This cognitive functional recovery may be a consequence of a reduction in Aβ accumulation through the inhibition of β- and γ-secretase activities, without altering α-secretase activity. Significance Here, we investigated the mechanism by which p75 NTR regulates Aβ production and accumulation. Better understanding the relationship between p75 NTR and Aβ producing may help taking insight into the AD pathology.