Date of Award
Doctor of Philosophy
Prior research supports a strong link between Alzheimer’s disease (AD) and metabolic dysfunction that involves a multi-directional interaction between glucose, glutamatergic homeostasis and amyloid pathology. Elevated soluble amyloid-beta (Aβ) is an early biomarker for AD-associated cognitive decline before plaque deposition that contributes to concurrent glutamatergic and metabolic dyshomeostasis in humans and male transgenic (AβPP/PS1) AD mice. High-fat diet studies have demonstrated worsening of glutamatergic and amyloid pathologies with glucose dysregulation. Yet, it remains unclear how primary time-sensitive targeting of hippocampal glutamatergic activity may impact glucose regulation in an amyloidogenic mouse model. Riluzole is a neuroprotective agent thought to restore hippocampal glutamatergic tone and improve spatial cognition in AD mice with prodromal administration. Previous studies have illustrated upregulation of glucose uptake and metabolism with riluzole treatment, supporting the link between glucose and glutamatergic homeostasis. Targeting of early glutamatergic hyperexcitation through riluzole treatment could aid in attenuating co-occurring metabolic and amyloidogenic pathologies with the intent of ameliorating cognitive decline. To that end, we conducted an early intervention study in transgenic (AβPP/PS1) and knock-in (APPNL-F/NL-F) AD mice to assess the on- and off- treatment effects of prodromal glutamatergic modulation (2-6 months of age) on glucose homeostasis and spatial cognition through riluzole treatment. The addition of the APPNL-F/NL-F knock-in mouse model aided in avoiding confounding variables associated with transgenic mice, such as overexpression of the amyloid precursor protein and presenilin-1. Separately, we performed in vivo glutamate recordings in a cohort of APPNL-F/NL-F mice to characterize hippocampal glutamatergic dynamics with age, as this has not been previously characterized in this model and provides further context to the outcomes of our early intervention study. Thus, our central hypotheses were that (1) APPNL-F/NL-F mice would exhibit presymptomatic hippocampal glutamatergic hyperactivation similar to AβPP/PS1 mice that shifts with age and disease progression and (2) prodromal riluzole treatment in AβPP/PS1 and APPNL-F/NL-F mice would attenuate glutamatergic and metabolic dysfunction producing on- and off-treatment procognitive effects. Glutamate recordings supported elevated stimulus-evoked glutamate release in the DG and CA3 of young (2-4 months old) APPNL-F/NL-F male mice that declined with age (18+ months old) compared to age-matched control mice. Young female APPNL-F/NL-F mice exhibited increased glutamate clearance in the CA1 that slowed with age compared to age-matched control mice. Male and female APPNL-F/NL-F mice displayed decreased basal glutamate levels in the CA1, while males also showed depletion in the CA3. Cognitive assessment demonstrated impaired spatial cognition in aged male and female APPNL-F/NL-F mice, but only aged females displayed recognition memory deficits compared to age-matched control mice. These findings confirm a sex-dependent hyper-to-hypoactivation glutamatergic paradigm in APPNL-F/NL-F mice. Further, data illustrated a sexually dimorphic biological aging process resulting in a more severe cognitive phenotype for female APPNL-F/NL-F mice than their male counterparts. Research outcomes mirrored that of human AD pathology and provide further evidence of divergent AD pathogenesis between sexes. Early glutamatergic modulation with riluzole treatment yielded improved peripheral glucose tolerance on-treatment for APPNL-F/NL-F and C57BL/6 male mice alone compared to genotype-matched vehicle-treated controls. Prodromal riluzole treatment also conferred off-treatment procognitive effects in male APPNL-F/NL-F and AβPP/PS1 mice compared to their respective controls. On-treatment effects for female mice indicated improved insulin tolerance for riluzole-treated C57BL/6 female mice alone than genotype-matched vehicle-treated mice. Further, improved spatial learning performance on-treatment was only observed for female AβPP/PS1 mice compared to respective control mice. Similar to the male APPNL-F/NL-F mice, female APPNL-F/NL-F riluzole-treated mice displayed improved spatial long-term memory performance off-treatment than genotype-matched vehicle-treated mice. Together, these results indicated a sex- and genotype-specific effect on glucose homeostasis and spatial cognition with riluzole intervention that evolved with disease progression and time since treatment. These findings support the interconnected nature of glucose and glutamatergic homeostasis with amyloid pathology and petition for further investigation into targeting of this relationship to improve cognitive performance.
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