Dr. Victoria Mgbemena recently led a team of multidisciplinary researchers (Dr. Kim - PVAMU, Dr. Ali - TAMU, Dr. Darwish - AgriLife) to earn a TAMUS REF Early Stage Development Grant. This is a 1-year, $100,000, TAMUS internal grant to significantly elevate research capacity, competitiveness, and impact across the A&M System.

Project Title: Targeting and Characterization of Alzheimer’s Disease by a Novel Fyn Kinase Inhibitor

Principal Investigator: Victoria Mgbemena, Ph.D. Co-PIs:

• Dr. Seungchan Kim (Co-PI, PVAMU)
• Dr. Hamed I. Aly Ismail (Co-PI, TAMU)
• Dr. Ahmed Darwish (Co-PI, AgriLife)

Project Summary:

Overview of Proposed Research Concept: Alzheimer’s disease (AD) is a progressive neurodegenerative disorder and the leading cause of dementia, accounting for 60-80% of cases and projected to affect ∼13 million Americans by 2050 (Kelliny S. et al., 2025, Alzheimer’s Association, 2023,Centers for Disease Control and Prevention [CDC], 2024, Alzheimer’s Association, 2025). Despite recent advances in amyloid-targeting antibodies, including lecanemab and donanemab (Tassinari & Milelli, 2025), no therapy effectively reverses the synaptic dysfunction underlying cognitive decline (Daly et al., 2024, Papaliagkas, 2025, Kim et al., 2025, Wang et al., 2025). Thus, innovative mechanisms that directly target early synaptic failure are critically needed. AD neuropathology is characterized by amyloid-β (Aβ) plaques, tau neurofibrillary tangles (TNFs), synaptic loss, and neuroinflammation (Bloom, 2014). A key pathway driving synaptic dysfunction in AD is the tau/Fyn/N-methyl-D-aspartate receptor (NMDAR) axis. Under normal conditions, tau recruits the Src-family kinase Fyn to postsynaptic sites to modulate NMDAR signaling (Fan et al., 2022). The Fyn kinase belongs to a family of proteins important for signal transduction across multiple cellular pathways, including immune cell activation of T-cells and B-cells (Thomas & Brugge, 1997; Salmond et al., 2009; Banerjee et al., 2013). In AD, mislocalized tau aberrantly scaffolds Fyn within dendritic spines (Ittner et al., 2010; Chin et al., 2005), promoting GluN2B-Y1472 phosphorylation and driving NMDAR over-activation. This triggers $\text{Ca}^{2+}$-dependent excitotoxicity, synaptic dysfunction, tau hyperphosphorylation, and Aβ secretion (Fan et al., 2022, Peng & Fu, 2023; van Dyck et al., 2019; Guglietti et al., 2021). Genetic and in vivo evidence show that tau-dependent Fyn signaling functionally links Aβ-toxicity to synaptic collapse and AD pathology. While amyloid burden shows weak correlation with clinical symptoms, tau pathology and synaptic degeneration closely track with disease severity (Bloom, 2014; Fan et al., 2022; Thomas & Brugge, 1997, Ittner et al., 2010), highlighting synapses as high-value therapeutic targets. This project targets Fyn kinase, a non-receptor tyrosine kinase and key mediator of synaptic toxicity induced by Aβ and Tau. There is currently a noteworthy potential drug which targets Fyn kinase known as AZD0530, saracatinib. Saracatinib is currently being repurposed for efficacy testing in AD in preclinical and clinical tests. So far in these tests, it has been shown to rescue memory, restore synaptic density and reduce microglial activation in AD mouse models (Martínez-Mármol et al., 2023; Yadikar et al., 2020). Dr. Hamed Ali’s team has identified a high-potential small-molecule candidate (AB157) with high predicted blood-brain barrier (BBB) penetrability. We will test the lead compound using a human 3D vascularized forebrain organoid model. By integrating iPSC-derived neural/mesenchymal aggregates, we will create a physiologically relevant “humanized” system to evaluate the reduction of pathogenic Aβ and Tau phosphorylation without systemic cytotoxicity. The goal of this project is to investigate and understand molecular shifts over time in the presence and absence of our team’s Fyn kinase inhibitor.

Alignment with State, National Research Priorities: Our research aligns directly with the National Institute on Aging (NIA) and National Institutes of Health (NIH) goals to increase the development of effective treatments for AD and related dementias (ADRD). Our project addresses a local public health challenge relating to an aging population, and targets specific biological mechanisms of Aging and Dementia. It also aligns well with strategic goals of the Dementia Prevention Research Institute of Texas (DPRIT).

Anticipated Impact: It is crucial for society to investigate and understand the etiology of AD , so that prevention and treatment strategies can lessen the burden on families and the health care system. The successful completion of this project will provide an effective pipeline construct for drug screening, testing and evaluation, and provide a pathway between in vitro modeling and preclinical mouse studies.