Sex- and age-specific modulation of brain GABA levels in a mouse model of Alzheimer's disease

• DOI: 10.1016/j.neurobiolaging.2017.10.015
• Publication Date: 2017-10-27T01:01:18Z
• Authors: Upasana Roy; Lara Stute; Corinna Höfling; Maike Hartlage-Rü...; Jörg Matysik; Steffen Roβner; A. Alia
• Keywords: Male; Aging; Memory Disorders; Sex Characteristics; Magnetic Resonance Spectroscopy; Brain; Amyloidogenic Proteins; Mice, Transgenic; 3. Good health; Disease Models, Animal; 03 medical and health sciences; 0302 clinical medicine; Alzheimer Disease; Risk Factors; Astrocytes; Putrescine; Animals; Female; Longitudinal Studies; Monoamine Oxidase; gamma-Aminobutyric Acid

Age and sex are risk factors of Alzheimer's disease (AD). Among the neurotransmitter systems, gamma-aminobutyric acid (GABA) has been implicated in AD pathogenesis but the relevance of sex-specific GABAergic dysfunction during AD progression remains unknown. In the present study, we utilized state-of-the-art high-resolution magic angle spinning nuclear magnetic resonance to systematically monitor the brain region-, age-, and sex-specific modulation of GABA levels in wild-type and Tg2576 mice with amyloid pathology. In addition, we followed the possible role of reactive astrocytes in sex-specific GABA modulation. In female Tg2576 mice, hippocampal GABA levels were significantly elevated, along with higher number of reactive astrocytes and amyloid deposition. The elevated GABA was found to be produced via the monoamine oxidase-B route from putrescine in reactive astrocytes, more substantially in female than male mice, thus suggesting a role of astrocytes in memory impairment and sex-related differences in AD. Our results paint a coherent model of memory impairment in AD and signify that dynamic changes in regional GABA may be at the root of marked sex disparities observed in AD.