# Endocannabinoids in Neurodegenerative Diseases

> **NIH NIH R01** · UNIVERSITY OF TEXAS HLTH SCIENCE CENTER · 2021 · $386,665

## Abstract

Summary
While the etiology of Alzheimer's disease (AD) is multifactorial and complex, results from epidemiological,
clinical, and laboratory animal studies implicate traumatic brain injury (TBI) as an important risk factor for AD
and dementia. However, the mechanisms by which TBI increases the risk of AD are largely unknown. In
particular, there are no effective therapies to prevent or treat TBI-caused AD neuropathology and dementia.
Accumulating evidence suggests that neuroinflammation following the primary injury plays a critical factor in
secondary brain damage and subsequent neuropathological changes. Therefore, resolving neuroinflammation
will significantly reduce secondary brain damage and eventually prevent or reduce the incidence of TBI-
induced AD-like neurodegenerative disease. Endogenous cannabinoids display anti-inflammatory and
neuroprotective properties. During the current period of funding, we provided evidence that monoacylglycerol
lipase (MAGL), the key enzyme that metabolizes the endocannabinoid 2-arachidonoylglycerol (2-AG) in the
brain, is likely a new therapeutic target for AD. Pharmacological inactivation of MAGL reduces neuropathology
and improves synaptic plasticity and memory formation in animal models of both TBI and AD. However, we do
not know whether genetic disruption of MAGL will yield beneficial effects similar to those following
pharmacological inhibition of MAGL in TBI. In addition, there is a gap in our knowledge about the signaling
pathways that mediate anti-inflammatory and neuroprotective effects produced by MAGL inhibition in TBI. In
this competing renewal application, we propose to test our hypothesis that alleviation of TBI-induced AD-like
neuropathological changes by pharmacological or genetic disruption of MAGL is primarily mediated by
enhancement of 2-AG signaling in astrocytes, which, in turn curbs neuroinflammation. Thus, the primary
objective of the studies proposed in this application will use our established mouse model of repetitive mild
closed head injury to demonstrate that inhibition of 2-AG metabolism by pharmacological inhibition or genetic
disruption of MAGL ameliorates AD-like neuropathology, improves recovery of synaptic and cognitive
functions, and halts disease progression and delineate the signaling pathways that mediate the beneficial
effects produced by MAGL inhibition. The results from this project may ultimately lead to development of a
novel therapeutic intervention for TBI-induced AD-like neurodegenerative disease.

## Key facts

- **NIH application ID:** 10161865
- **Project number:** 5R01NS076815-10
- **Recipient organization:** UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
- **Principal Investigator:** CHU CHEN
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $386,665
- **Award type:** 5
- **Project period:** 2012-06-15 → 2023-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10161865

## Citation

> US National Institutes of Health, RePORTER application 10161865, Endocannabinoids in Neurodegenerative Diseases (5R01NS076815-10). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10161865. Licensed CC0.

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