PROJECT SUMMARY Owing to the aging of populations worldwide, Alzheimer’s disease (AD) is reaching epidemic proportions, with a large social and economic burden. While the most notable symptom of AD is the severe memory loss, patients with AD also suffer from neuropsychiatric symptoms, including impaired sociability and aggression, which represent significant challenges to the care for these patients. Unfortunately, the mechanisms underlying these neuropsychiatric deficits during AD pathogenesis remain to be fully understood and effective treatments are limited. The brain 5-hydroxytryptamine (5-HT, serotonin) regulates multiple physiological functions, including the control of anger, aggression, mood and cognition. Interestingly, numerous studies reported that the brains of AD patients display extensive “5-HT denervation”, as demonstrated by reduced 5-HT neuron numbers or 5-HT bioavailability. These suggest that impaired brain 5-HT signaling contributes to certain AD symptoms. We identified several loss-of-function point mutations in the human HTR2C gene, encoding 5-HT 2C receptor (5-HT2CR), from individuals with cognitive deficits and social incompetence. We generated a knock-in mouse model, Htr2cF327L, to mimic one such mutation and found that these mutant mice recapitulate human symptoms, including impaired memory, decreased sociability and increased aggression. Given the similarity between the Htr2cF327L-induced phenotypes and those seen in AD, we tested effects of lorcaserin (a selective 5-HT2CR agonist) in an amyloid precursor AppNL-G-F knock-in AD mouse model. Interestingly, lorcaserin ameliorates cognitive and neuropsychiatric deficits in AppNL-G-F mice, associated with enhanced neural plasticity in the ventral hippocampal CA1 (vCA1). These findings led to a general hypothesis that the 5-HT/5-HT2CR signaling ameliorates cognitive and social behaviors in AD. To test this hypothesis, we will first combine the retrograde chemogenetics and loss- or gain-of-function mouse models to determine the role of the 5-HT→vCA1 circuit in cognition, sociability and aggression in health and AD pathogenesis. Using site-specific gene manipulation and the humanized genetic mouse models, we will also determine the role of vCA1 5-HT2CRs in cognition, sociability and aggression in health and AD pathogenesis. Finally, we will test lorcaserin effects in two pre-clinical AD models (with distinct pathogenic mechanisms): AppNL-G-F and PS19. Importantly, we will test these mice at various ages along the disease progression to determine the crucial time window for this pharmacological strategy to be most effective. Results obtained from these studies are expected to advance our understanding about the fundamental biology of cognitive/social behaviors and the neurobiology of human AD progression. In addition, these studies carry significant translational values and will provide a framework for novel therapeutic strategies to ameliorate cognitive and neuropsychiatric symptoms in AD.

PROJECT NARRATIVE Brains from Alzheimer’s patients often display loss of 5-HT neurons, but the causal relationship of this 5-HT dysregulation and Alzheimer’s symptoms is unclear. In the proposed research, we will determine whether the dysregulated 5-HT→hippocampus circuit contributes to the cognitive and neuropsychiatric symptoms in AD and further test whether a 5-HT receptor (5-HT2CR) is a suitable target for therapeutic interventions.