Abstract
Apolipoprotein (apo) E4 is the major genetic risk factor for Alzheimer's disease (AD). ApoE4 has sex-dependent effects, whereby the risk of developing AD is higher in apoE4-expressing females than males. However, the mechanism underlying the sex difference, in relation to apoE4, is unknown. Previous findings indicate that apoE4 causes age-dependent impairments of hilar GABAergic interneurons in female mice, leading to learning and memory deficits. Here, we investigate whether the detrimental effects of apoE4 on hilar GABAergic interneurons are sex-dependent using apoE knock-in (KI) mice across different ages. We found that in female apoE-KI mice, there was an age-dependent depletion of hilar GABAergic interneurons, whereby GAD67- or somatostatin-positive–but not NPY- or parvalbumin-positive–interneuron loss was exacerbated by apoE4. Loss of these neuronal populations was correlated with the severity of spatial learning deficits at 16 months of age in female apoE4-KI mice; however, this effect was not observed in female apoE3-KI mice. In contrast, we found an increase in the numbers of hilar GABAergic interneurons with advancing age in male apoE-KI mice, regardless of apoE genotype. Moreover, male apoE-KI mice showed a consistent ratio of hilar inhibitory GABAergic interneurons to excitatory mossy cells approximating 1.5 that is independent of apoE genotype and age, whereas female apoE-KI mice exhibited an age-dependent decrease in this ratio, which was exacerbated by apoE4. Interestingly, there are no apoE genotype effects on GABAergic interneurons in the CA1 and CA3 subregions of the hippocampus as well as the entorhinal and auditory cortexes. These findings suggest that the sex-dependent effects of apoE4 on developing AD is in part attributable to inherent sex-based differences in the numbers of hilar GABAergic interneurons, which is further modulated by apoE genotype.
Highlights
Alzheimer’s disease (AD) is a common age-dependent neurodegenerative disease characterized by progressive and irreversible cognitive decline [1,2]
As parvalbumin-positive interneurons in the hippocampus are essential for spatial working memory [44], we examined whether the numbers of parvalbumin-positive GABAergic interneurons in the hilus of the dentate gyrus were changed in apoE-KI mice as a function of age, sex, or apoE genotype
Our data revealed that independent of apoE genotype, male apoE-KI mice had an age-dependent increase in the number of hilar GABAergic interneurons while female apoE-KI mice demonstrated an age-dependent decrease, due in part to sex-specific GABAergic interneurogenesis in the hilus of aged male apoE-KI mice that is little or absent in aged female apoE-KI mice
Summary
Alzheimer’s disease (AD) is a common age-dependent neurodegenerative disease characterized by progressive and irreversible cognitive decline [1,2]. Epidemiological studies that focus on disease prevalence as a measure of risk have presented mixed results in regards to sex susceptibility to AD [3,4,5], which may be confounded by the higher longevity of woman compared to men. Apolipoprotein (apo) E4, found in 65–80% of late onset sporadic and familial AD cases, is the predominant genetic risk factor, and its expression increases the occurrence and lowers the age of onset of AD in a gene dose-dependent manner [12,13,14]. Epidemiological studies have further indicated a sex-specific association with respect to the apoE4 allele, whereby women expressing this allele have a higher risk of being affected by AD than men, regardless of longevity and disease mortality factors [14,15,16,17,18,19].
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