CXPT, USC Mann School of Pharmacy & Pharmaceutical Sciences, PSC 504, 1985 Zonal Ave. Los Angeles, California 90089

	ABSTRACT

 Alzheimer’s disease (AD) is a neurodegenerative condition characterized by cognitive decline and memory loss. The current lack of understanding regarding the cause of AD has impeded the development of animal models for drug testing, resulting in a dearth of effective prevention and treatment methods. Despite efforts to target Aβ plaques and tau protein tangles, which have proven ineffective, it is evident that these factors alone do not fully account for the cognitive deficits and memory loss associated with AD. While clinical trials seek effective treatments, success remains uncertain.
  Recent attempts to reduce Aβ levels in Alzheimer’s disease treatment have proven ineffective, indicating that Aβ plaques and tau protein tangles are not the sole contributors to cognitive deficits and memory loss. Drugs such as rivastigmine and varenicline have demonstrated no significant benefits in treating Alzheimer’s patients. Although memantine is employed for mild cognitive impairment, a comprehensive analysis reveals limited improvement in cognitive function and a potential risk of gastrointestinal adverse reactions. Clinical trials continue in the pursuit of effective treatments, with outcomes remaining uncertain.
  Upon examining AD symptoms, it was observed that 70% of patients exhibited anxiety/ depression, 17% experienced epileptic seizures, and 60 to 90% faced sleep disorders. These issues point towards dysfunction in the GABA system in AD patients, yet the precise role of GABA in AD pathogenesis remains unclear. GABA, a major inhibitory neurotransmitter, plays a crucial role in initiating and regulating sleep, participating in cognitive formation, and managing anxiety and depression. It collaborates with excitatory neurons to maintain a balance in the brain. Our development of dihydromyricetin (DHM), a positive modulator of GABA, aims to address these imbalances.
  Research indicates that symptoms such as depression, anxiety, and sleep disorders manifest 15 to 20 years before an AD diagnosis. Social isolation or loneliness has been identified as a factor contributing to a 50% increase in AD incidence. To replicate the natural onset of AD, we created social isolation animal models that effectively mimic human social isolation. After a 4-week isolation period, we observed increased Aβ plaques and tau tangles, reduced mitochondrial ATP production, heightened neuroinflammation, and anxiety/ depression/aggression. Post-synaptic gephyrin and GABAergic neurotransmitter activity were reduced, accompanied by cognitive impairment. Notably, DHM was able to reverse these pathological changes.
  Social isolation also induced neuroinflammation, affecting the tripartite synapses formed by astrocytes and neurosynapses, fundamental to cognitive formation. Astrocytes support neurosynapses’ structure and function, maintaining cognitive processes. However, even two weeks of social isolation led to astrocyte atrophy and damage to the tripartite synaptic structure, resulting in cognitive impairment.
  This study provides compelling evidence that tripartite synapses form the basis of cognition, and damage to tripartite synapses is a key mechanism for cognitive impairment. The DHM we developed demonstrates unprecedented efficacy in reshaping tripartite synapses, representing a groundbreaking discovery.
  We posit that DHM has the potential to evolve into an effective drug for the prevention and treatment of Alzheimer’s disease..

	INDEX

• Jing Liang. (2023) Breakthroughs in Alzheimer’s Disease Drug Vevelopment, in Editor M. Baudry (Ed.), IABS Forum 2023 (p. 8-9). International Association of Biomedical Sciences (IABS). DOI: 10.59566/iabs.2023.p008