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

Abstract

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.

Degeneration of the Suprachiasmatic Nucleus in an Alzheimer’s Disease Mouse Model Monitored by in vivo Magnetic Resonance Relaxation Measurements and Immunohistochemistry

“…Interestingly, the decline in hippocampal T2 relaxation time was more significant in female as compared to male Tg2576 mice. These results are in line with higher Aβ plaque load in hippocampus of female mice as compared to male mice seen in our previous studies [37]. On the other hand, in the thalamus region, which was associated with very low Aβ deposition [30], no significant change in T2 values between wild-type and Tg2576 mice was observed.…”

“…Clearly, the T2 values of the hippocampus, cingulate and piriform cortex of the 18 month old Tg2576 mice showed a significant decrease as compared to the agematched wild-type mice. The decline in hippocampal T2 relaxation time was more significant in female as compared to male Tg2576 mice [23,30,37]. In the thalamus region, T2 values did not show any significant change between wild-type and Tg2576 mice.…”

Astrocytic proBDNF and Tonic GABA Distinguish Active versus Reactive Astrocytes in Hippocampus

“…At the core of the aberrant GABA production, monoamine oxidase-b (MAO-B), mainly expressed in astrocytes, was shown to mediate the degradation of putrescine, a polyamine byproduct of degradation of amyloid beta (Aβ) toxin, and the biosynthesis of GABA in Aβ-overproducing AD model of APP/PS1 mice [ 6 ]. These findings were recently recapitulated and further expanded to show sex- and age-dependent expression pattern of GABA and actions of MAO-B in another animal model of AD, Tg2576 mice [ 9 ]. Based on these previous studies, the astrocytic GABA has been proposed as a molecular signature of reactive astrocytes when combined with astrocytic hypertrophy.…”

Quantification of aminobutyric acids and their clinical applications as biomarkers for osteoporosis

“…BABA is a natural product of plants controlled by the plant's immune system important for the treatment of various plant diseases 4 ; however, there are no associations between BABA and human diseases. GABA is a major inhibitory neurotransmitter in the central nervous system that regulates communication between neurons, and it is implicated in behavior, cognition, oxidative stress, glucose tolerance, and pathological conditions such as Alzheimer's disease and diabetes 5,6 . Studies in MCK-PGC1α (muscle-specific overexpression of peroxisome proliferator-activated receptor gamma coactivator 1-α) mice demonstrated that GABA levels in both plasma and skeletal muscles significantly increased following exercise.…”

“…active agents within the previous 6 months: Calcitonin, Estrogen, SERM, Depo-Provera, Denosumab, Evista; (4) systemic corticosteroid for more than 6 months duration or any corticoid therapy within the previous 6 months; (5) anticonvulsant therapy within the previous year; and (6) anyone with surgical fixation (metal).…”