You might recall that gene therapy to overexpress caveolin-1 in the brain was recently shown to reduce pathology in a mouse model of Alzheimer’s disease. In today’s open access paper, researchers apply the same gene therapy to a mouse model of TDP-43 pathology in the aging brain. In this model, the mice express higher than normal levels of TDP-43, and thus as they age, the animals exhibit greater levels of altered forms of TDP-43 that form aggregates and disrupt cell biochemistry in the brain as a consequence. This pathological aggregation and its consequences are particularly important in amyotrophic lateral sclerosis (ALS) and the recently named limbic-predominant age-related TDP-43 encephalopathy (LATE), but it seems likely that TDP-43 aggregation contributes in some way to all of the major named age-related neurodegenerative conditions.
Of note, the viral vector used in these studies, AAV-PHP.eB, is a relatively recently developed AAV serotype that allows for both intravenous injection and efficient transduction of cells in the brain. From a logistics and cost perspective, this is a large improvement over the need for stereotactic approaches to direct injection of the brain and intrathecal injections, and is spurring more interest in the development brain targeted gene therapies.
The mechanism by which increased caveolin-1 expression improves function in a brain undergoing neurodegenerative issues is quite interesting; it seems more suited to TDP-43 pathology than Alzheimer’s pathology, as one might argue that it is actually doing something to mitigate much of the core problem of TDP-43 alteration and mislocalization, rather than only compensating for root causes by enabling greater synaptic plasticity, as seems more the case in the Alzheimer’s disease models.
Transactive response DNA-binding protein 43 (TDP-43) proteinopathy is associated with frontotemporal dementia and Alzheimer’s disease (AD). We previously demonstrated that synapsin–promoted caveolin-1 (SynCav1) preserves cognitive function in the mouse model of AD. This study investigated the therapeutic potential of SynCav1 in a mouse model of TDP-43 proteinopathy. AAV-PhP.eB-SynCav1 was delivered systemically to the TDP-43A315T mouse, followed by cognitive evaluation and biochemical and ultrastructural analysis of brain tissue.
Systemic AAV-PhP.eB-SynCav1 gene therapy efficiently crossed the blood-brain barrier and achieved central nervous system-wide neuroprotection. Mechanistically, pathological TDP-43 mislocalized to membrane lipid rafts (MLRs), resulting in decreased MLR-associated GluN2A expression and degenerative changes in neuronal ultrastructure. In contrast, SynCav1 delivery alleviated TDP-43 mislocalization on MLRs, stabilized MLR-associated GluN2A expression, and preserved synaptic ultrastructure. Furthermore, SynCav1 mitigated TDP-43-induced mitochondrial hyper-fragmentation and excessive mitochondrial fission signaling.
These findings establish a novel link between TDP-43 proteinopathy and MLR instability, supporting SynCav1 as a “neuron-centric” candidate for treating TDP-43-related neurodegeneration.
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