| First Author | Devi L | Year | 2010 |
| Journal | PLoS One | Volume | 5 |
| Issue | 9 | Pages | e12974 |
| PubMed ID | 20886088 | Mgi Jnum | J:165103 |
| Mgi Id | MGI:4836282 | Doi | 10.1371/journal.pone.0012974 |
| Citation | Devi L, et al. (2010) Phospho-eIF2alpha level is important for determining abilities of BACE1 reduction to rescue cholinergic neurodegeneration and memory defects in 5XFAD mice. PLoS One 5(9):e12974 |
| abstractText | beta-Site APP-cleaving enzyme 1 (BACE1) initiates amyloid-beta (Abeta) generation and thus represents a prime therapeutic target in treating Alzheimer's disease (AD). Notably, increasing evidence indicates that BACE1 levels become elevated in AD brains as disease progresses; however, it remains unclear how the BACE1 upregulation may affect efficacies of therapeutic interventions including BACE1-inhibiting approaches. Here, we crossed heterozygous BACE1 knockout mice with AD transgenic mice (5XFAD model) and compared the abilities of partial BACE1 reduction to rescue AD-like phenotypes at earlier (6-month-old) and advanced (15-18-month-old) stages of disease, which expressed normal ( approximately 100%) and elevated ( approximately 200%) levels of BACE1, respectively. BACE1(+/-) deletion rescued memory deficits as tested by the spontaneous alternation Y-maze task in 5XFAD mice at the earlier stage and prevented their septohippocampal cholinergic deficits associated with significant neuronal loss. Importantly, BACE1(+/-) deletion was no longer able to rescue memory deficits or cholinergic neurodegeneration in 5XFAD mice at the advanced stage. Moreover, BACE1(+/-) deletion significantly reduced levels of Abeta42 and the beta-secretase-cleaved C-terminal fragment (C99) in 6-month-old 5XFAD mouse brains, while these neurotoxic beta-cleavage products dramatically elevated with age and were not affected by BACE1(+/-) deletion in 15-18-month-old 5XFAD brains. Interestingly, although BACE1(+/-) deletion lowered BACE1 expression by approximately 50% in 5XFAD mice irrespective of age in concordance with the reduction in gene copy number, BACE1 equivalent to wild-type controls remained in BACE1(+/-).5XFAD mice at the advanced age. In accord, phosphorylation of the translation initiation factor eIF2alpha, an important mediator of BACE1 elevation, was dramatically increased ( approximately 9-fold) in 15-18-month-old 5XFAD mice and remained highly upregulated ( approximately 6-fold) in age-matched BACE1(+/-).5XFAD mice. Together, our results indicate that partial reduction of BACE1 is not sufficient to block the phospho-eIF2alpha-dependent BACE1 elevation during the progression of AD, thus limiting its abilities to reduce cerebral Abeta/C99 levels and rescue memory deficits and cholinergic neurodegeneration. |
