Knock-In of Human BACE1 Cleaves Murine APP and Reiterates Alzheimer-like Phenotypes

Abstract

Key neuropathological hallmarks of Alzheimer's disease (AD) are elevated levels of amyloid ␤-peptide (A␤) species generated via amyloid precursor protein (APP) endoproteolysis and cleavage by the rate-limiting ␤-site enzyme 1 (BACE1). Because rodents do not develop amyloid pathologies, we here investigated whether AD-like endophenotypes can be created in mice by expression of human bace1. To avoid pitfalls of existing models, we introduced hbace1 via knock-in under the control of the CaMKII ␣ promoter into the safe HPRT locus.We report amyloidogenic processing of murine APP in the hBACE1 mice (termed PLB4), resulting in the formation of toxic APP metabolites that accumulate intra-and extraneuronally in hippocampus and cortex. Pronounced accumulation of A␤*56 and A␤ hexamers in the absence of plaque deposition was detected in brain tissue from symptomatic PLB4 mice. Heightened levels of inflammation (gliosis) also appeared in several AD-related brain regions (dentate gyrus, hippocampal area CA1, piriform and parietal cortices) at 6 and 12 months of age. Behaviorally, deficits in habituation to a novel environment and semantic-like memory (social transmission of food preference) were detected from 3 to 4 months of age. Impairments in spatial learning strategies in long-term reference (water maze) and working memory (Y-maze) tasks presented at 6 months, and were distinct from reductions in locomotor activity and anxiety.Overall, our data indicate for the first time that targeted, subtle forebrain-specific expression through single gene knock-in of hBACE1 is sufficient to generate AD-relevant cognitive impairments amid corresponding histopathologies, confirming human BACE as the key parameter in amyloid pathogenesis.

Progressive age-related changes in sleep and EEG profiles in the PLB1Triple mouse model of Alzheimer’s disease

“…In support of this, soluble Ab accumulation has also been proposed to play the key role human AD pathogenesis (Gouras et al, 2000;Lesné et al, 2006Lesné et al, , 2013. Previous data from our PLB lines confirmed that soluble Ab and potentially tau fragments are key players in AD neurodegeneration (see also Pluci nska et al, 2014) and, therefore, suggest that soluble species may play a vital role in sleep-wakefulness disturbances.…”

“…For data acquired over time, a repeated-measures ANOVA was applied. Habituation behavior was further probed using a 1-phase decay fit and statistically compared using the extra sum of squares F test based on plateau and K values as parameters (for details, see Pluci nska et al, 2014).…”

“…Analysis of motor activity assessed for the first 3 hours (in 10-minute bins) can serve as an indicator of explorative behavior and acquisition of spatial information (Pluci nska et al, 2014). However, as ambulatory activity is intrinsically affected by age, the time course of habituation cannot serve as an absolute measure for spatial capabilities and must be controlled for per age group.…”

Being human: The role of pluripotent stem cells in regenerative medicine and humanizing Alzheimer's disease models

“…There is a report that overexpression of wild type (WT) human tau in a tau knockout background can lead to NFTs, implying that mouse tau might be inhibitory to the process (Andorfer et al, 2003). In addition, a recent study demonstrated that a knockin of human BACE1 enhanced murine Aβ production and was sufficient to cause cognitive deficits, suggesting that regulators of APP processing are also different in mice (Plucinska et al, 2014). Overall this suggests that there are species-specific differences in APP and Tau and how the brain responds to mutant versions of FAD genes.…”

Disrupted-in-Schizophrenia-1 Attenuates Amyloid-β Generation and Cognitive Deficits in APP/PS1 Transgenic Mice by Reduction of β-Site APP-Cleaving Enzyme 1 Levels

“…20 Moreover, several neuropsychiatric symptoms, such as abnormalities in emotionality/activity, social interactions and sensomotor abilities are commonly detected in AD patients (Lyketsos et al, 2011). Deficits in working memory and social interactions that have been described for DISC1 mutant mice (Ayhan et al, 2011;Koike et al, 2006;Pletnikov et al, 2008) are also observed in BACE1 knock-in transgenic mice (Plucinska et al, 2014).…”