Abstract
β-Site APP-cleaving enzyme 1 (BACE1) initiates amyloid-β (Aβ) 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 (∼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 Aβ42 and the β-secretase-cleaved C-terminal fragment (C99) in 6-month-old 5XFAD mouse brains, while these neurotoxic β-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 ∼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 eIF2α, an important mediator of BACE1 elevation, was dramatically increased (∼9-fold) in 15–18-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-eIF2α-dependent BACE1 elevation during the progression of AD, thus limiting its abilities to reduce cerebral Aβ/C99 levels and rescue memory deficits and cholinergic neurodegeneration.
Highlights
The cause of Alzheimer’s disease (AD) has not been completely understood, there is increasing consensus that accumulation of the amyloid-b (Ab) peptide plays a central role in triggering a pathogenic cascade leading to neuronal death and profound memory deficits [1,2]
When mice were tested at 15–18 months of age, levels of spontaneous alternation was reduced in 5XFAD and b-Site amyloid precursor protein (APP)-cleaving enzyme 1 (BACE1)+/2?5XFAD mice compared with those of age-matched wild-type control mice (F(3,33) = 11.38, p,0.05) (Fig. 1B)
Emerging evidence suggests that partial reduction of BACE1, which is induced by BACE1+/2 gene deletion [21,22], siRNA targeting BACE1 [18] and immunization with BACE1 ectodomain [19], can diminish brain Ab levels and amyloid-related pathologies and improve synaptic and cognitive dysfunctions in different APP transgenic mice
Summary
The cause of Alzheimer’s disease (AD) has not been completely understood, there is increasing consensus that accumulation of the amyloid-b (Ab) peptide plays a central role in triggering a pathogenic cascade leading to neuronal death and profound memory deficits [1,2]. The bsecretase (BACE1: b-site amyloid precursor protein cleaving enzyme 1), which is responsible for initiating the production of Ab, represents an excellent therapeutic target for the treatment of AD [3,4,5,6]. This view is strongly supported by a growing body of evidence that genetic deletion of BACE1 prevents AD-like pathologies and improves cognitive impairments in different transgenic mouse models [7,8,9,10]. Given that central lowering of Ab levels following systemic administration of future BACE1 inhibitor drugs may be limited [16,17], it is important to determine the degree of BACE1 suppression that is required to exert therapeutic benefits including memory improvements during the progression of AD
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