| First Author | Honda K | Year | 2024 |
| Journal | Sci Rep | Volume | 14 |
| Issue | 1 | Pages | 18471 |
| PubMed ID | 39122814 | Mgi Jnum | J:353365 |
| Mgi Id | MGI:7710599 | Doi | 10.1038/s41598-024-69400-9 |
| Citation | Honda K, et al. (2024) Suppression of the amyloidogenic metabolism of APP and the accumulation of Abeta by alcadein alpha in the brain during aging. Sci Rep 14(1):18471 |
| abstractText | Generation and accumulation of amyloid-beta (Abeta) protein in the brain are the primary causes of Alzheimer's disease (AD). Alcadeins (Alcs composed of Alcalpha, Alcbeta and Alcgamma family) are a neuronal membrane protein that is subject to proteolytic processing, as is Abeta protein precursor (APP), by APP secretases. Previous observations suggest that Alcs are involved in the pathophysiology of Alzheimer's disease (AD). Here, we generated new mouse App(NL-F) (APP-KI) lines with either Alcalpha- or Alcbeta-deficient background and analyzed APP processing and Abeta accumulation through the aging process. The Alcalpha-deficient APP-KI (APP-KI/Alcalpha-KO) mice enhanced brain Abeta accumulation along with increased amyloidogenic beta-site cleavage of APP through the aging process whereas Alcbeta-deficient APP-KI (APP-KI/Alcbeta-KO) mice neither affected APP metabolism nor Abeta accumulation at any age. More colocalization of APP and BACE1 was observed in the endolysosomal pathway in neurons of APP-KI/Alcalpha-KO mice compared to APP-KI and APP-KI/Alcbeta-KO mice. These results indicate that Alcalpha plays an important role in the neuroprotective function by suppressing the amyloidogenic cleavage of APP by BACE1 in the brain, which is distinct from the neuroprotective function of Alcbeta, in which p3-Alcbeta peptides derived from Alcbeta restores the viability in neurons impaired by toxic Abeta. |
