PROJECT SUMMARY Alzheimer’s disease (AD) is a progressive neurodegenerative disorder that is characterized by the accumulation of neurofibrillary plaques and tangles, cognitive decline, mood and behavior changes, and dementia. Despite the recent FDA approval of Leqembi, limited progress has been made towards identifying more efficacious AD treatments, underscoring the need for new treatment strategies. Compared to the general population, patients with AD have a significantly higher incidence of epilepsy, and the risk for developing epilepsy is even higher in patients with early-onset AD. Furthermore, over 40% of AD patients without a history of epilepsy exhibit subclinical epileptiform activity. This overlap between epilepsy and AD suggests a shared underlying disease mechanism, and we propose that this commonality may be leveraged to guide novel treatment strategies. Mutations that increase activity of SCN8A (which encodes the voltage-gated sodium channel Nav1.6) are associated with epilepsy and a range of behavioral abnormalities. Interestingly, increased Nav1.6 expression has also been observed in brains from AD patients and mouse models of AD. We hypothesize that increased SCN8A activity in AD contributes to multiple clinically challenging features of AD, including epileptiform discharges, cognitive impairment, and AD neuropathology. Consistent with this hypothesis, Yuan et al. recently reported reduced Ab plaques and amelioration of cognitive and synaptic deficits following hippocampal knockdown of Nav1.6 in 5-month-old male APP/PS1 mutants, and SCN8A was recently nominated as a potential therapeutic target for AD (Agora AD knowledge portal). Hyperexcitability and tau neuropathology in AD originate in the locus coeruleus (LC), and the LC is anatomically and functionally connected to other vulnerable brain regions that develop AD pathology, including the hippocampus which is also critical for seizure generation and cognitive behavior. Furthermore, degeneration of the LC is a pervasive characteristic of mid- to late-stage AD and contributes to the progression of forebrain pathology and cognitive impairment. In our Preliminary data, we show that Scn8a is highly expressed in the LC, suggesting an important role for Scn8a in the LC. As Nav1.6 is located at the axon initial segment and regulates neuronal excitability, we predict that reducing Nav1.6 in the LC may prevent or delay hyperexcitability of the LC, which in turn, may prevent or slow the development of multiple AD phenotypes. Thus, targeting SCN8A in the LC may provide a novel therapeutic opportunity to prevent disease progression in AD. In the proposed studies, we will establish the effect of selectively SCN8A knockdown in the LC or hippocampus on seizure susceptibility, epileptiform activity, behavior, and AD neuropathology.

PROJECT NARRATIVE Many patients with Alzheimer’s disease (AD) have an increased risk of developing epilepsy, and over 40% of AD patients without a history of epilepsy exhibit subclinical epileptiform activity. Increased expression of the voltage-gated sodium channel SCN8A has been observed in brains from AD patients and mouse models of AD, and we speculate that increased Nav1.6 activity in AD contributes to multiple clinically challenging features of AD, including epileptiform discharges, cognitive impairment, and AD neuropathology. We will use genetic, behavioral, and electrophysiological, approaches to establish the beneficial effects of selectively reducing SCN8A expression in AD.