Adeno-associated virus-based Alzheimer's disease mouse models and potential new therapeutic avenues

Abstract

Alzheimer's disease (AD) is a highly prevalent neurodegenerative condition that presents with cognitive decline. The current understanding of underlying disease mechanisms remains incomplete. Genetically modified mouse models have been instrumental in deciphering pathomechanisms in AD. While these models were typically generated by classical transgenesis and genome editing, the use of adeno-associated viruses (AAVs) to model and investigate AD in mice, as well as to develop novel gene-therapy approaches, is emerging. Here, we reviewed literature that used AAVs to study and model AD and discuss potential gene therapy strategies. LINKED ARTICLES: This article is part of a themed section on Therapeutics for Dementia and Alzheimer's Disease: New Directions for Precision Medicine. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v176.18/issuetoc.

Figure 1

Potential of AAV in advancing AD studies and therapies. Combining AAV with either wild‐type (non‐transgenic) or established genetically modified lines (including AD models) offers the opportunity to generate new AD models and interrogate existing AD models to understand underlying disease mechanisms. Furthermore, AAV has been used to interfere with pathological processes in AD mouse models, establishing proof‐of‐concept for potential gene therapies

Figure 2

Different modes of delivering AAV for CNS gene expression in mice. (a) Common methods reported for delivering AAV‐mediated gene expression in neonatal mice include (A) direct stereotaxic brain infusion, (B) spinal cord injections, and (C) intravascular delivery. (b) Techniques most frequently reported for delivering AAV‐mediated gene expression in mature mice include (D) direct stereotaxic brain infusion, (E) spinal cord injections, (F) intravascular, and (G) i.m. delivery. (c) Two commonly used methods for intracerebral delivery of AAV in adult brains are (H) intracerebrovascular injection for widespread gene expression or (I) into distinct brain areas for localized expression. Both techniques require the use of stereotaxic devices for guided injections