Increasing synaptic PSD-95, a neuroprotection approach against Alzheimer's disease

University Of California, San Diego, La Jolla CA

Investigators

Linked publications, trials & patents

Abstract

Project Summary/Abstract The first change in the brains of patients with Alzheimer’s and the best biomarker of the disease is synaptic loss. Several studies have shown that PSD-95 (a major scaffolding protein at the synapse) is significantly depleted in brain tissue from patients with Alzheimer’s as well as in neurons exposed to Aβ. Our data indicate that elevated synaptic PSD-95 blocks Aβ-induced synaptic depression. The amount of synaptic PSD-95 is controlled by a process called ‘palmitoylation’ which mediate the insertion of PSD-95 in post-synaptic membranes. Using a commercially available inhibitor of PSD-95 depalmitoylating enzyme, Palmostatin B, we showed that this drug could rescue Aβ-mediated effects on dendritic spines in vitro. In female APP/PS1 mice, we found that in the hippocampus, palmitoylated PSD-95 was significantly lower than in WT littermates while total PSD-95 levels were barely affected. Importantly, Palmostatin B injections in the intraperitoneal cavity rescued this effect in a dose dependent manner, indicating that this drug can access brain synapses in vivo. The key focus of the parent grant is thus to test the potential of a novel drug target, PSD-95 depalmitoylating enzyme, as a new therapeutic avenue against Alzheimer’s disease (AD). To do so, we proposed several different experiments, some of which were completed in the first 3.5 years of the grant. However, some key experiments still need to be completed and due to unforeseen circumstances, require this Administrative Supplement. In some of the research described in Aims 1 and 2, fluorescence lifetime imaging (FLIM) experiments were proposed to understand how Aβ reduces synaptic PSD-95 (Aim 1.2), to test if increasing other synaptic scaffolding proteins can also protect synapses from Aβ (Aim 1.3) and determine if Palmostatin B can rescue Aβ-induced changes in PSD-95 interactions (Aim 2.3). These experiments require a functional two-photon laser and our laser unexpectedly broke in September 2024. This Administrative Supplement would allow us to replace our laser, complete these key experiments and continue to use and develop FLIM to understand molecular mechanisms in synaptic physiology as our lab is one of the world’s leaders using FLIM in neuroscience research. Moreover, in Aim 3, we proposed behavioral experiments to assess if Palmostatin B can rescue memory deficits in vivo. Characterizing the effect of a drug on mouse behavior is the most convincing way of demonstrating therapeutic potential. These experiments were planned with Dr. Rissman, a leader in AD model mouse research. Dr. Rissman unexpectedly left UCSD in June 2024, making it impossible for us to use his behavioral equipment. To complete these essential experiments, we need to purchase our own behavioral equipment, which would be possible with this Administrative Supplement. Importantly, all the proposed research in this Administrative Supplement request is to complete experiments originally planned in the main grant, and thus within its scope. In conclusion, this innovative project will improve our understanding of how synapses are affected during AD and test a pharmacological approach to make synapses stronger from within, which would be beneficial for both treating and preventing AD.