Lentivirus-mediated expression of human secreted amyloid precursor protein-alpha prevents development of memory and plasticity deficits in a mouse model of Alzheimer's disease

Abstract

Alzheimer’s disease (AD) is a neurodegenerative disease driven in large part by accumulated deposits in the brain of the amyloid precursor protein (APP) cleavage product amyloid-β peptide (Aβ). However, AD is also characterised by reductions in secreted amyloid precursor protein-alpha (sAPPα), an alternative cleavage product of APP. In contrast to the neurotoxicity of accumulated Αβ, sAPPα has many neuroprotective and neurotrophic properties. Increasing sAPPα levels has the potential to serve as a therapeutic treatment that mitigates the effects of Aβ and rescue cognitive function. Here we tested the hypothesis that lentivirus-mediated expression of a human sAPPα construct in a mouse model of AD (APPswe/PS1dE9), begun before the onset of plaque pathology, could prevent later behavioural and electrophysiological deficits. Male mice were given bilateral intra-hippocampal injections at 4 months of age and tested 8–10 months later. Transgenic mice expressing sAPPα performed significantly better than untreated littermates in all aspects of the spatial water maze task. Expression of sAPPα also resulted in partial rescue of long-term potentiation (LTP), tested in vitro. These improvements occurred in the absence of changes in amyloid pathology. Supporting these findings on LTP, lentiviral-mediated expression of sAPPα for 3 months from 10 months of age, or acute sAPPα treatment in hippocampal slices from 18 to 20 months old transgenic mice, completely reversed the deficits in LTP. Together these findings suggest that sAPPα has wide potential to act as either a preventative or restorative therapeutic treatment in AD by mitigating the effects of Aβ toxicity and enhancing cognitive reserve.

Inhibition of DREAM-ATF6 interaction delays onset of cognition deficit in a mouse model of Huntington’s disease

“…The novel object recognition test was performed as reported [ 21 , 22 ]. In brief, mice were first individually habituated to the open-field for 50 min.…”

Hippocampal Deficits in Amyloid-β-Related Rodent Models of Alzheimer’s Disease

“…Chronic intranasal administration of Colivelin (a novel and strong humanin derivative) reduced amyloid-β deposition in the hippocampus, rescued suppression of hippocampal LTP, and prevented AD-associated behavioral impairments in APP/PS1 mice (Wu et al, 2017). In addition, increasing levels of the secreted APPα (sAPPα, an alternative cleavage product of APP that has neuroprotective and neurotrophic properties) completely reversed deficits in LTP and spatial memory tasks in APP Swe /PS1 E9 mice (Tan et al, 2018). Therefore, it is important to keep in mind the protective roles of some biproducts of APP (for a review see Montagna et al, 2017), although the pathological biproducts of APP are often the focus in AD literature.…”

Glutamate Receptor Trafficking and Protein Synthesis Mediate the Facilitation of LTP by Secreted Amyloid Precursor Protein-Alpha

“…This latter feature is conserved across mammalian (Meziane et al, 1998), avian (Mileusnic et al, 2004), and invertebrate (Bourdet et al, 2015) species. Furthermore, sAPP␣ rescues LTP and memory impairments in Alzheimer's mouse models (Fol et al, 2016;Tan et al, 2018), in mouse knock-outs of APP expression, or with ␣-secretase inhibition (Ring et al, 2007;Taylor et al, 2008;Hick et al, 2015;Moreno et al, 2015;Fol et al, 2016;Richter et al, 2018). Together, these data indicate that sAPP␣ plays a critical role in LTP, but the molecular mechanisms engaged by sAPP␣ to regulate LTP are not yet understood.…”