Gene-Dose-Dependent Reduction Fshr Expression Improves Spatial Memory Deficits in Alzheimer's Mice

Area of Science:

• Neuroscience
• Endocrinology
• Genetics

Background:

• Alzheimer's disease (AD) is a progressive neurodegenerative disorder linked to aging.
• Elevated post-menopausal follicle-stimulating hormone (FSH) levels correlate with AD onset.
• FSH directly activates hippocampal FSH receptors (Fshr), driving AD pathology and memory loss in mice.

Approach:

• Used female 3xTg mice with varying Fshr gene dosages (Fshr+/+, Fshr+/-, Fshr-/-).
• Administered ovariectomy or sham surgery, with estradiol normalization in some groups.
• Assessed spatial and recognition memory using Morris Water Maze and Novel Object Recognition tests.

Key Points:

• Fshr depletion dose-dependently prevented spatial memory impairment in 3xTg mice.
• Deletion of Fshr protected against age-related progression of spatial memory deficits.
• Recognition memory loss was prevented by Fshr deletion, except in ovariectomized mice.
• Amyloid β40 levels were reduced in a gene-dose-dependent manner with Fshr depletion.
• Low serum FSH levels correlated with better spatial memory retrieval in aged APP/PS1 mice.

Conclusions:

• Genetic evidence supports a protective role for inhibiting FSH signaling in memory deficits.
• FSH receptor signaling contributes to AD-like cognitive decline and pathology.
• Targeting FSH signaling offers a potential strategy for early prevention of cognitive decline in postmenopausal women.