Apolipoprotein E4 Causes Age- and Sex-Dependent Impairments of Hilar GABAergic Interneurons and Learning and Memory Deficits in Mice

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.

Cognitive Deficits and Disruption of Neurogenesis in a Mouse Model of Apolipoprotein E4 Domain Interaction

“…In all figures white bars represent C57BL/6J and black bars represent Arg-61 mice. the female mice, in line with the greater risk in women to develop AD and an apparently greater effect of apoE4 in impairing spatial memory performance in females (32,63,64). This observation is consistent with numerous studies in apoE4 subjects showing that the role of apoE4 in cognitive function extends beyond the AD disease state, which apoE4 gene clearly impacts.…”

Apolipoprotein E: Structure and function in lipid metabolism, neurobiology, and Alzheimer's diseases

“…ApoE4 knock-in mice show an age-dependent decrease in hilar GABAergic interneurons, which correlates with the extent of apoE4-induced impairments of adult hippocampal neurogenesis and with learning and memory deficits (Andrews-Zwilling et al, 2010; Leung et al, 2012; Li et al, 2009). In transgenic mice expressing neurotoxic apoE4 fragments, the loss of hilar interneurons is more pronounced and also correlates with learning and memory deficits (Andrews-Zwilling et al, 2010).…”

“…Morphological studies of these transgenic mouse lines demonstrated that human apoE3 prevents the age-dependent neurodegeneration seen in apoE-null mice and prevents kainic acid–induced neurodegeneration; human apoE4 is not protective (Buttini et al, 1999). ApoE4 knock-in mice also show age- and sex-dependent impairment of spatial learning and memory (Andrews-Zwilling et al, 2010; Leung et al, 2012). Transgenic mice expressing apoE4 in astrocytes had impairment of working memory, although no significant neuropathological changes were found in the brains of these mice (Hartman et al, 2001).…”

Potential of GABA-ergic cell therapy for schizophrenia, neuropathic pain, and Alzheimer׳s and Parkinson׳s diseases

“…Furthermore, decreases in GABA and SST levels are more pronounced in apoE4 carriers (accounting for 60-75% of AD patients) exhibiting enhanced brain activity at rest and in response to memory tasks (Grouselle et al, 1998;Filippini et al, 2009;Dennis et al, 2010). Moreover, the expression of apoE4 in mice causes an age-and sex-dependent (female>-male) decrease in hilar GABAergic interneurons, which correlates with the severity of learning and memory deficits (Andrews-Zwilling et al, 2010; Leung et al, 2012). Likewise, increased production or aggregation of Aβ interferes with interneuron function and leads to abnormal DG activity and cognitive impairments (Verret et al, 2012).…”