Beneficial Effects of the β-Secretase Inhibitor GRL-8234 in 5XFAD Alzheimer’s Transgenic Mice Lessen During Disease Progression

Abstract

The β-secretase enzyme BACE1, which initiates the cleavage of amyloid precursor protein (APP) into the amyloid-β (Aβ) peptide, is a prime therapeutic target for Alzheimer’s disease (AD). However, recent investigations using genetic animal models raise concern that therapeutic BACE1 inhibition may encounter the dramatic reduction of efficacy in ameliorating AD-like pathology and memory deficits during disease progression. Here, we compared the effects of the potent and selective small-molecule BACE1 inhibitor GRL-8234 in different pathological stages of AD mouse model. Specifically, we administered GRL-8234 (33.4 mg/kg, i.p.) once daily for 2 months to 5XFAD transgenic mice, which showed modest (4 months) and massive (10 months of age) Aβ plaque deposition at starting points. Chronic treatments with GRL-8234 reversed memory impairments, as tested by the spontaneous alternation Y-maze task, in the younger 5XFAD group concomitant with significant reductions in cerebral Aβ42 levels. In contrast, only marginal reductions of Aβ42 were observed in 12-month-old 5XFAD mice treated with GRL-8234 and their memory function remained impaired. We found that not only BACE1 but also full-length APP expression was significantly elevated with progressive Aβ accumulation in 5XFAD mice, while GRL-8234 failed to affect these detrimental mechanisms that further accelerate plaque growth in brains of older 5XFAD mice. Therefore, our results provide important insights into the mechanisms by which Aβ accumulation and related memory impairments become less responsive to rescue by BACE1 inhibition during the course of AD development.

Longitudinal measures of cognition in the Ts65Dn mouse: Refining windows and defining modalities for therapeutic intervention in Down syndrome

“…Ts65Dn mice are characterized by a number of phenotypes including progressive loss of working memory, cholinergic deficit in the basal forebrain, neuroinflammation, and endosomal and brain amyloid precursor protein abnormalities, all of which have been observed in AD and mouse models of AD (Hartley et al, 2015). The current findings of impairments in nesting behavior, spontaneous alternation and reversal learning are also consistent with findings in mouse models of AD (Filali and Lalonde, 2009; Morales-Corraliza et al, 2013; Torres-Lista and Gimenez-Llort, 2013; Webster et al, 2014; Devi et al, 2015). Moreover, inflexibility of learning is an early feature of AD dementia (Albert, 1996; Traykov et al, 2007), further linking Ts65Dn as a mouse model of AD.…”

Effects of BACE1 haploinsufficiency on APP processing and Aβ concentrations in male and female 5XFAD Alzheimer mice at different disease stages

“…Meanwhile, BACE1 may be in excess over APP in 5XFAD males with lower transgenic APP overexpression (~160%) so that 50% BACE1 reduction has little effect on lowering Aβ. In this study, we found no difference in APP expression levels between male and female 5XFAD mice, and APP overexpression relative to wild-type control levels in the 5XFAD model (Tg6799 line) was much higher (300–500%) in a series of previous investigations including ours (Oakley et al, 2006, Ohno et al, 2007, Hong et al, 2013, Devi and Ohno, 2014, Py et al, 2014, Devi et al, 2015). The results using well-established anti-APP antibodies against the C-terminus (C1/6.1) and N-terminus (22C11) are consistent in these studies.…”

“…We hypothesize that the C83 reduction found in BACE1 +/− ·5XFAD mice may reflect a secondary change that occurs as a consequence of prior C99 reduction. This view is supported by our recent pharmacological data demonstrating that administration of the β-secretase inhibitor GRL-8234 to 5XFAD mice induced C83 lowering concomitant with C99 reductions (Devi et al, 2015). The results are also consistent with clinical observations that the C-terminally truncated short fragments of Aβ, which are released by sequential β- and α-cleavage of APP, are elevated in AD compared to non-demented controls and their concentrations change in accordance with the availability of the substrate C99 (e.g., increase by γ-secretase inhibition) (Portelius et al, 2006, Portelius et al, 2010, Portelius et al, 2011).…”

“…Moreover, it should be noted that BACE1 +/− knockout mice show no or only marginal reductions (10–20%) of endogenous Aβ40 as compared with wild-type controls (Pastorino et al, 2004, Nishitomi et al, 2006, Sankaranarayanan et al, 2008, Rabe et al, 2011). In this regard, while pharmacological data demonstrate that chronic treatments with bioavailable small-molecule BACE1 inhibitors (e.g., GRL-8234 and TAK-070) in preventive settings improve memory impairments concomitant with significant cerebral Aβ reductions in 5XFAD as well as Tg2576 mice (Fukumoto et al, 2010, Chang et al, 2011, Devi et al, 2015), it would be important to further evaluate their therapeutic efficacy in APP knock-in mice that circumvent APP overexpression (Webster et al, 2013, Li et al, 2014, Saito et al, 2014) and thus may be less responsive to rescue by partial BACE1 inhibition.…”

Inhibiting BACE1 to reverse synaptic dysfunctions in Alzheimer’s disease

“…The brain-penetrable BACE1 inhibitor GRL-8234 showed a rapid decrease in soluble Aβ in the brain of Tg-2576 mice, and long-term treatment up to 7.5 months rescued cognitive defects induced by Aβ in this mouse model (Chang et al, 2011). Once-daily injection of an improved BACE1 inhibitor, GRL-8234, for 2 months showed clear improvements in memory tests in 5xFAD AD mice (Devi et al, 2015). A six-month treatment regimen of Tg-2576 mice with another BACE1 inhibitor, TAK70, also showed decreased cerebral Aβ deposition by approximately 60% and ameliorated memory deficits (Fukumoto et al, 2010).…”