Targeting PSD-95 palmitoylation in Alzheimer’s disease

Conférence du Centre de recherche CERVO
Date et heure: 
Ven, 2021-12-17 11:00
Une conférence de: 
Kim Doré
Description: 

The first change in the brains of patients with Alzheimer’s disease (AD) and the best biomarker of the disease is synaptic loss. The molecular pathways preceding synaptic loss during AD are still unclear but mounting evidence suggest that loss of PSD-95 is one of the first events leading to synaptic loss as it is significantly depleted in the brains AD patients as well as in neurons exposed to amyloid-beta (Aβ). We discovered that elevated levels of PSD-95 (under a number of different conditions) can protect against, and even reverse, synaptic weakening by Aβ. Because PSD-95 requires palmitoylation to remain at a synapse, we tested if pharmacological blockade of PSD-95 depalmitoylating enzyme, ABHD17, could increase synaptic resilience. In vitro experiments showed that Palmostatin B (an ABHD17 inhibitor), could rescue Aβ-induced synaptic depression and Aβ-mediated effects on dendritic spines. Interestingly, we saw that PSD-95 palmitoylation is significantly reduced in APP/PS1 mice, which might indicate a previously unknown step in the pathophysiology of AD. Palmostatin B injections in the intraperitoneal cavity rapidly rescued palmitoylated PSD-95 in a dose dependent manner in APP/PS1 mice, indicating that this drug can access brain synapses in vivo. Furthermore, preliminary data suggests that Palmostatin B can rescue memory deficits in the Morris Water Maze behavioral test. Consequently, PSD-95 depalmitoylating enzyme could be an exciting new drug target against AD.

 

Participer à la réunion Zoom

https://us06web.zoom.us/j/86452156384?pwd=clRlYmN0K2N0OFJZU0NQUjRyQkQ2Zz09
ID de réunion : 864 5215 6384
Code secret : 044882

Local: 
F-1455 et via Zoom
Lieu: 
Centre de recherche CERVO Brain Research Centre, 2601, de la Canardière Québec (Québec) CANADA G1J 2G3

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