Basic Science and Pathogenesis

Area of Science:

• Neuroscience
• Biochemistry
• Pathology

Background:

• Alzheimer's disease (AD) is linked to inflammation and mitochondrial dysfunction, impacting synaptic integrity.
• Metabolic dysfunction is a proposed driver of neuroinflammation and synaptic damage in AD.
• Investigating sex-specific differences is crucial, as post-menopausal females have a higher prevalence of AD.

Purpose of the Study:

• To compare metabolic, synaptic, and inflammatory markers in human Alzheimer's disease (AD) brains versus age-matched controls.
• To identify sex-specific differences in these markers, given the higher AD prevalence in females.
• To explore the role of metabolic dysfunction and inflammation in AD pathogenesis.

Main Methods:

• Analysis of prefrontal cortex samples from post-mortem donors (10 per sex and condition).
• Utilized immunofluorescence, western blot, ELISA for cytokine panels, and mitochondrial respiration assays.
• Examined markers of Akt/mTOR signaling, mitochondrial complexes, synaptic proteins, inflammation (IL-2, Iba-1), and microglial morphology.

Main Results:

• Alzheimer's disease (AD) brains exhibited altered Akt phosphorylation and increased mitochondrial complex III and V content.
• AD females showed reduced Complex IV respiration, while both sexes had altered synaptic marker expression (AMPA GluA1, synaptophysin).
• Sex-specific differences were observed, with greater metabolic signaling changes in females and altered Iba-1 expression in AD females.

Conclusions:

• Significant differences in Akt signaling and mitochondrial content exist in the prefrontal cortex of AD donors.
• Metabolic signaling dysregulation in AD appears to be more pronounced in females, suggesting a unique female-specific pathway.
• These findings highlight the complex interplay of metabolic, inflammatory, and synaptic changes in AD pathogenesis, with notable sex differences.