| RRC ID |
81597
|
| Author |
Honda K, Takahashi H, Hata S, Abe R, Saito T, Saido TC, Taru H, Sobu Y, Ando K, Yamamoto T, Suzuki T.
|
| Title |
Suppression of the amyloidogenic metabolism of APP and the accumulation of Aβ by alcadein α in the brain during aging.
|
| Journal |
Sci Rep
|
| Abstract |
Generation and accumulation of amyloid-β (Aβ) protein in the brain are the primary causes of Alzheimer's disease (AD). Alcadeins (Alcs composed of Alcα, Alcβ and Alcγ family) are a neuronal membrane protein that is subject to proteolytic processing, as is Aβ 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 AppNL-F (APP-KI) lines with either Alcα- or Alcβ-deficient background and analyzed APP processing and Aβ accumulation through the aging process. The Alcα-deficient APP-KI (APP-KI/Alcα-KO) mice enhanced brain Aβ accumulation along with increased amyloidogenic β-site cleavage of APP through the aging process whereas Alcβ-deficient APP-KI (APP-KI/Alcβ-KO) mice neither affected APP metabolism nor Aβ accumulation at any age. More colocalization of APP and BACE1 was observed in the endolysosomal pathway in neurons of APP-KI/Alcα-KO mice compared to APP-KI and APP-KI/Alcβ-KO mice. These results indicate that Alcα 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 Alcβ, in which p3-Alcβ peptides derived from Alcβ restores the viability in neurons impaired by toxic Aβ.
|
| Volume |
14(1)
|
| Pages |
18471
|
| Published |
2024-8-9
|
| DOI |
10.1038/s41598-024-69400-9
|
| PII |
10.1038/s41598-024-69400-9
|
| PMID |
39122814
|
| PMC |
PMC11316129
|
| MeSH |
Aging* / metabolism
Alzheimer Disease / genetics
Alzheimer Disease / metabolism
Amyloid Precursor Protein Secretases* / metabolism
Amyloid beta-Peptides* / metabolism
Amyloid beta-Protein Precursor* / genetics
Amyloid beta-Protein Precursor* / metabolism
Animals
Aspartic Acid Endopeptidases / genetics
Aspartic Acid Endopeptidases / metabolism
Brain* / metabolism
Calcium-Binding Proteins / genetics
Calcium-Binding Proteins / metabolism
Mice
Mice, Knockout
Nerve Tissue Proteins / genetics
Nerve Tissue Proteins / metabolism
Neurons / metabolism
|
| IF |
3.998
|
| Resource |
| Mice |
RBRC06343 |
