%0 Journal Article
%T Phospho-eIF2¦Á Level Is Important for Determining Abilities of BACE1 Reduction to Rescue Cholinergic Neurodegeneration and Memory Defects in 5XFAD Mice
%A Latha Devi
%A Masuo Ohno
%J PLOS ONE
%D 2012
%I Public Library of Science (PLoS)
%R 10.1371/journal.pone.0012974
%X ¦Â-Site APP-cleaving enzyme 1 (BACE1) initiates amyloid-¦Â (A¦Â) 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¨C18-month-old) stages of disease, which expressed normal (~100%) and elevated (~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 A¦Â42 and the ¦Â-secretase-cleaved C-terminal fragment (C99) in 6-month-old 5XFAD mouse brains, while these neurotoxic ¦Â-cleavage products dramatically elevated with age and were not affected by BACE1+/£¿ deletion in 15¨C18-month-old 5XFAD brains. Interestingly, although BACE1+/£¿ deletion lowered BACE1 expression by ~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 eIF2¦Á, an important mediator of BACE1 elevation, was dramatically increased (~9-fold) in 15¨C18-month-old 5XFAD mice and remained highly upregulated (~6-fold) in age-matched BACE1+/£¿¡¤5XFAD mice. Together, our results indicate that partial reduction of BACE1 is not sufficient to block the phospho-eIF2¦Á-dependent BACE1 elevation during the progression of AD, thus limiting its abilities to reduce cerebral A¦Â/C99 levels and rescue memory deficits and cholinergic neurodegeneration.
%U http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0012974