Exogenous rGDF11 ameliorates chronic stress-induced cognitive impairment by suppressing the accumulation of...

Chronic unpredictable mild stress (CUMS) is a well-established model for studying stress-induced cognitive impairment. Emerging evidence suggests that dysregulation of endogenous formaldehyde (FA) metabolism in the hippocampus contributes to such impairment, yet therapeutic strategies targeting this pathway remain limited. Growth differentiation factor 11 (GDF11), a neuroprotective protein, has been implicated in synaptic regulation and cognitive function, but its direct roles in modulating chronic stress-induced cognitive impairment and FA homeostasis under chronic stress remain unknown.

Adult male Sprague-Dawley rats were subjected to CUMS for 4 weeks. During the last two weeks, rats received intracerebroventricular injections of recombinant GDF11 (rGDF11) at doses of 0.4, 1.2, or 4.0 ng/kg. Cognitive performance was assessed using the Y-maze, novel object recognition (NOR) test, and Morris water maze (MWM). Hippocampal tissue was analyzed for FA levels using a fluorescence probe, and protein expression of synaptic markers (SYN-1, PSD-95) and FA-metabolizing enzymes (SSAO, ADH5, ALDH2) was measured by Western blot.

CUMS-exposed rats showed significant cognitive deficits across all behavioral tests, along with downregulation of synaptic proteins, elevated hippocampal FA levels, and imbalances in the expression of FA-metabolizing enzymes. Treatment with rGDF11, particularly at 4.0 ng/kg, dose-dependently restored synaptic protein expression and normalized FA metabolism by downregulating SSAO and upregulating ADH5 and ALDH2.

Exogenous rGDF11 ameliorates CUMS-induced cognitive impairment by suppressing hippocampal FA accumulation and restoring synaptic integrity through regulation of FA-metabolizing enzymes. These findings identify GDF11 as a potential therapeutic target for stress-related cognitive disorders.