Promoting adult hippocampal neurogenesis in Alzheimer's Disease Models

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Project Summary Adult Hippocampal Neurogenesis (AHN) is critical for normal learning and memory and reduced AHN is an early hallmark of Alzheimer’s Disease (AD). Thus, restoring AHN has emerged as an attractive target for AD therapy. The accumulation of negative signals that degrade the neurogenic niche contributes to the reduction in newborn neurons in AD and aging. BMPs are components of the niche that negatively regulate neurogenesis and their levels are increased in AD in humans and in mouse FAD models. We recently reported that full length MuSK harboring its Ig3 domain, which is necessary for high affinity BMP binding, is a BMP co-receptor that augments and shapes BMP signaling. In preliminary studies we established that MuSK is endogenously expressed in neural stem cells (NSCs). We generated knock-in mice engineered to constitutively express an alternatively spliced form of MuSK lacking the Ig3 domain (‘ΔIg3- MuSK’). The animals are viable, fertile and have a normal life span. NSCs isolated from ΔIg3- MuSK mice show impaired BMP responsiveness. Remarkably, the ΔIg3-MuSK mice exhibit over a two-fold increase in AHN and improved hippocampal-dependent learning. These results suggest that reducing MuSK-BMP activity by modulating MuSK alternative splicing is a potential target for promoting AHN in AD. Importantly, such alternative splicing is expected to be amenable to manipulation by exon-skipping antisense oligonucleotides. The recent success of the ASO Spinraza for Spinal Muscular Atrophy has demonstrated that this class of drugs can be highly effective in the human CNS, with a favorable pharmacokinetic and safety profile. In the proposed experiments we will use mouse FAD models to test whether inhibition of the MuSK- BMP pathway can promote AHN in the plaque-rich and inflammatory ‘AD environment’. To more closely model the pathological and therapeutic landscape in humans, we will also use conditional mutants to test whether manipulating the MuSK-BMP pathway after amyloid plaque formation can promote AHN and improve cognition. If successful, this work will form an important part of the rationale and impetus for a pursuing a MuSK-directed ASO therapy for AD.