# 5-HT 2C Receptor and Alzheimer's Disease

> **NIH NIH R01** · BAYLOR COLLEGE OF MEDICINE · 2024 · $558,372

## Abstract

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 sym...

## Key facts

- **NIH application ID:** 10928224
- **Project number:** 5R01AG080392-02
- **Recipient organization:** BAYLOR COLLEGE OF MEDICINE
- **Principal Investigator:** YONG XU
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $558,372
- **Award type:** 5
- **Project period:** 2023-09-15 → 2028-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10928224

## Citation

> US National Institutes of Health, RePORTER application 10928224, 5-HT 2C Receptor and Alzheimer's Disease (5R01AG080392-02). Retrieved via AI Analytics 2026-05-28 from https://api.ai-analytics.org/grant/nih/10928224. Licensed CC0.

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