Viral gene transfer of APPsα rescues synaptic failure in an Alzheimer’s disease mouse model

Nov 6, 2015Acta neuropathologica

Using a viral gene to restore brain cell connections in a mouse model of Alzheimer's disease

AI simplified

Longevity & Aging on OpenScience ↗PubMed ↗DOI ↗

Abstract

Sustained overexpression of APPsα in aged AD model mice restored synaptic plasticity and improved spatial memory.

Overexpression of APPsα was achieved through AAV-mediated gene transfer in APP/PS1∆E9 mice.
This treatment partially rescued spine density deficits associated with Alzheimer's disease.
A significant reduction in soluble Aβ species and plaque load was observed after APPsα treatment.
APPsα treatment enhanced the recruitment of microglia around plaques, indicating potential plaque clearance.
Improvements in cognitive function were demonstrated in the Morris water maze, suggesting functional recovery.

AI simplified

Alzheimer's disease (AD) is characterized by synaptic failure, dendritic and axonal atrophy, neuronal death and progressive loss of cognitive functions. It is commonly assumed that these deficits arise due to β-amyloid accumulation and plaque deposition. However, increasing evidence indicates that loss of physiological APP functions mediated predominantly by neurotrophic APPsα produced in the non-amyloidogenic α-secretase pathway may contribute to AD pathogenesis. Upregulation of APPsα production via induction of α-secretase might, however, be problematic as this may also affect substrates implicated in tumorigenesis. Here, we used a gene therapy approach to directly overexpress APPsα in the brain using AAV-mediated gene transfer and explored its potential to rescue structural, electrophysiological and behavioral deficits in APP/PS1∆E9 AD model mice. Sustained APPsα overexpression in aged mice with already preexisting pathology and amyloidosis restored synaptic plasticity and partially rescued spine density deficits. Importantly, AAV-APPsα treatment also resulted in a functional rescue of spatial reference memory in the Morris water maze. Moreover, we demonstrate a significant reduction of soluble Aβ species and plaque load. In addition, APPsα induced the recruitment of microglia with a ramified morphology into the vicinity of plaques and upregulated IDE and TREM2 expression suggesting enhanced plaque clearance. Collectively, these data indicate that APPsα can mitigate synaptic and cognitive deficits, despite established pathology. Increasing APPsα may therefore be of therapeutic relevance for AD.

Full Text

Full text is available at the source.

View full text (PDF) ↗View full text (HTML) ↗View full text ↗

Viral gene transfer of APPsα rescues synaptic failure in an Alzheimer’s disease mouse model

Abstract

Full Text

You found one interesting study. We’ll send the next 7.

what lands in your inbox each week:

Recent issues from the longevity & aging brief