Abstract
BackgroundMutations in the PSEN1 and PSEN2 genes are the major cause of familial Alzheimer’s disease. Previous studies demonstrated that Presenilin (PS), the catalytic subunit of γ-secretase, is required for survival of excitatory neurons in the cerebral cortex during aging. However, the role of PS in inhibitory interneurons had not been explored.MethodsTo determine PS function in GABAergic neurons, we generated inhibitory neuron-specific PS conditional double knockout (IN-PS cDKO) mice, in which PS is selectively inactivated by Cre recombinase expressed under the control of the endogenous GAD2 promoter. We then performed behavioral, biochemical, and histological analyses to evaluate the consequences of selective PS inactivation in inhibitory neurons.ResultsIN-PS cDKO mice exhibit earlier mortality and lower body weight despite normal food intake and basal activity. Western analysis of protein lysates from various brain sub-regions of IN-PS cDKO mice showed significant reduction of PS1 levels and dramatic accumulation of γ-secretase substrates. Interestingly, IN-PS cDKO mice develop age-dependent loss of GABAergic neurons, as shown by normal number of GAD67-immunoreactive interneurons in the cerebral cortex at 2–3 months of age but reduced number of cortical interneurons at 9 months. Moreover, age-dependent reduction of Parvalbumin- and Somatostatin-immunoreactive interneurons is more pronounced in the neocortex and hippocampus of IN-PS cDKO mice. Consistent with these findings, the number of apoptotic cells is elevated in the cerebral cortex of IN-PS cDKO mice, and the enhanced apoptosis is due to dramatic increases of apoptotic interneurons, whereas the number of apoptotic excitatory neurons is unaffected. Furthermore, progressive loss of interneurons in the cerebral cortex of IN-PS cDKO mice is accompanied with astrogliosis and microgliosis.ConclusionOur results together support a cell-autonomous role of PS in the survival of cortical interneurons during aging. Together with earlier studies, these findings demonstrate a universal, essential requirement of PS in the survival of both excitatory and inhibitory neurons during aging.
Highlights
Mutations in the PSEN1 and PSEN2 genes are the major cause of familial Alzheimer’s disease
To generate inhibitory neuron-specific PS Inhibitory neuron-specific PS conditional double knockout (cDKO) (IN-PS cDKO) mice, we first crossed homozygous floxed PS1; PS2−/− mice [13] with GAD2-Internal ribosome entry site (IRES)-Cre recombinase (Cre) knockin (KI) mice (The Jackson Laboratory, 010802, RRID: IMSR_JAX:010802) [34] to obtain fPS1/+; PS2+/ −; GAD2-IRES-Cre/+ mice, which were bred with fPS1/fPS1; PS2−/− mice to generate fPS1/fPS1; PS2−/−; GAD2-IRES-Cre/+ (IN-PS cDKO) mice
Generation and molecular validation of IN-PS cDKO mice To investigate the normal physiological role of PS in inhibitory interneurons, we generated IN-PS cDKO mice, in which PS inactivation is restricted to inhibitory interneurons by the GAD2-IRES-Cre driver [34], resulting in Cre-mediated deletion of PS1 exons 2–3 [10, 13, 36]
Summary
Mutations in the PSEN1 and PSEN2 genes are the major cause of familial Alzheimer’s disease. Previous studies demonstrated that Presenilin (PS), the catalytic subunit of γ-secretase, is required for survival of excitatory neurons in the cerebral cortex during aging. Inherited mutations in the Presenilin genes (PSEN1 and PSEN2) account for ~ 90% of mutations identified in familial Alzheimer’s disease (FAD), highlighting their importance in the pathogenesis [1]. Presenilin-1 (PS1) and PS2 are highly expressed in neurons throughout development and in adulthood [2,3,4], and PS is the catalytic subunit of the γ-secretase complex [5]. It has been reported that the number of inhibitory neurons, especially PV- or SST-expressing interneurons, is reduced in various sub-regions of postmortem AD brains, such as the entorhinal cortex and the hippocampus [25,26,27,28,29,30,31]. Despite the importance of inhibitory neurons in AD pathogenesis, the role of PS in inhibitory neurons had not been studied
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