Hippocampal alterations in glutamatergic signaling during amyloid progression in AβPP/PS1 mice

Our previous research demonstrated that soluble amyloid-β (Aβ)42, elicits presynaptic glutamate release. We hypothesized that accumulation and deposition of Aβ altered glutamatergic neurotransmission in a temporally and spatially dependent manner. To test this hypothesis, a glutamate selective microelectrode array (MEA) was used to monitor dentate (DG), CA3, and CA1 hippocampal extracellular glutamate levels in 2–4, 6–8, and 18–20 month-old male AβPP/PS1 and age- matched C57BL/6J control mice. Starting at 6 months of age, AβPP/PS1 basal glutamate levels are elevated in all three hippocampal subregions that becomes more pronounced at the oldest age group. Evoked glutamate release was elevated in all three age groups in the DG, but temporally delayed to 18–20 months in the CA3 of AβPP/PS1 mice. However, CA1 evoked glutamate release in AβPP/PS1 mice was elevated at 2–4 months of age and declined with age. Plaque deposition was anatomically aligned (but temporally delayed) with elevated glutamate levels; whereby accumulation was first observed in the CA1 and DG starting at 6–8 months that progressed throughout all hippocampal subregions by 18–20 months of age. The temporal hippocampal glutamate changes observed in this study may serve as a biomarker allowing for time point specific therapeutic interventions in Alzheimer’s disease patients

Amyloid Beta-Related Alterations to Glutamate Signaling Dynamics During Alzheimer\u27s Disease Progression.

Alzheimer’s disease (AD) ranks sixth on the Centers for Disease Control and Prevention Top 10 Leading Causes of Death list for 2016, and the Alzheimer’s Association attributes 60% to 80% of dementia cases as AD related. AD pathology hallmarks include accumulation of senile plaques and neurofibrillary tangles; however, evidence supports that soluble amyloid beta (Aβ), rather than insoluble plaques, may instigate synaptic failure. Soluble Aβ accumulation results in depression of long-term potentiation leading to cognitive deficits commonly characterized in AD. The mechanisms through which Aβ incites cognitive decline have been extensively explored, with a growing body of evidence pointing to modulation of the glutamatergic system. The period of glutamatergic hypoactivation observed alongside long-term potentiation depression and cognitive deficits in later disease stages may be the consequence of a preceding period of increased glutamatergic activity. This review will explore the Aβ-related changes to the tripartite glutamate synapse resulting in altered cell signaling throughout disease progression, ultimately culminating in oxidative stress, synaptic dysfunction, and neuronal loss

Health disparities in aging: Improving dementia care for Black women

In the United States, 80% of surveyed Black patients report experiencing barriers to healthcare for Alzheimer\u27s disease and related dementias (ADRD), delaying the time-sensitive treatment of a progressive neurodegenerative disease. According to the National Institute on Aging, Black study participants are 35% less likely to be given a diagnosis of ADRD than white participants, despite being twice as likely to suffer from ADRD than their white counterparts. Prior analysis of prevalence for sex, race, and ethnicity by the Centers for Disease Control indicated the highest incidence of ADRD in Black women. Older (≥65 years) Black women are at a disproportionately high risk for ADRD and yet these patients experience distinct inequities in obtaining clinical diagnosis and treatment for their condition. To that end, this perspective article will review a current understanding of biological and epidemiological factors that underlie the increased risk for ADRD in Black women. We will discuss the specific barriers Black women face in obtaining access to ADRD care, including healthcare prejudice, socioeconomic status, and other societal factors. This perspective also aims to evaluate the performance of intervention programs targeted toward this patient population and offer possible solutions to promote health equity

Riluzole attenuates glutamatergic tone and cognitive decline in AβPP/PS1 mice.

We have previously demonstrated hippocampal hyperglutamatergic signaling occurs prior to plaque accumulation in AβPP/PS1 mice. Here, we evaluate 2-Amino-6-(trifluoromethoxy) benzothiazole (riluzole) as an early intervention strategy for Alzheimer\u27s disease (AD), aimed at restoring glutamate neurotransmission prior to substantial Beta amyloid (Aβ) plaque accumulation and cognitive decline. Male AβPP/PS1 mice, a model of progressive cerebral amyloidosis, were treated with riluzole from 2-6 months of age. Morris water maze, in vivo electrochemistry, and immunofluorescence were performed to assess cognition, glutamatergic neurotransmission, and pathology, respectively, at 12 months. Four months of prodromal riluzole treatment in AβPP/PS1 mice resulted in long-lasting procognitive effects and attenuated glutamatergic tone that was observed six months after discontinuing riluzole treatment. Riluzole-treated AβPP/PS1 mice had significant improvement in long-term memory compared to vehicle-treated AβPP/PS1 mice that was similar to normal aging C57BL/6J control mice. Furthermore, basal glutamate concentration and evoked-glutamate release levels, which were elevated in vehicle-treated AβPP/PS1 mice, were restored to levels observed in age-matched C57BL/6J mice in AβPP/PS1 mice receiving prodromal riluzole treatment. Aβ plaque accumulation was not altered with riluzole treatment. This study supports that interventions targeting the glutamatergic system during the early stages of AD progression have long-term effects on disease outcome, and importantly may prevent cognitive decline. Our observations provide preclinical support for targeting glutamate neurotransmission in patients at risk for developing AD

Prodromal Glutamatergic Modulation with Riluzole Impacts Glucose Homeostasis and Spatial Cognition in Alzheimer\u27s Disease Mice.

BACKGROUND: Prior research supports a strong link between Alzheimer\u27s disease (AD) and metabolic dysfunction that involves a multi-directional interaction between glucose, glutamatergic homeostasis, and amyloid pathology. Elevated soluble amyloid-β (Aβ) is an early biomarker for AD-associated cognitive decline that contributes to concurrent glutamatergic and metabolic dyshomeostasis in humans and male transgenic AD mice. Yet, it remains unclear how primary time-sensitive targeting of hippocampal glutamatergic activity may impact glucose regulation in an amyloidogenic mouse model. Previous studies have illustrated increased glucose uptake and metabolism using a neuroprotective glutamate modulator (riluzole), supporting the link between glucose and glutamatergic homeostasis. OBJECTIVE: We hypothesized that targeting early glutamatergic hyperexcitation through riluzole treatment could aid in attenuating co-occurring metabolic and amyloidogenic pathologies with the intent of ameliorating cognitive decline. METHODS: We conducted an early intervention study in male and female 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. RESULTS: 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. CONCLUSION: These findings support the interconnected nature of glucose and glutamatergic homeostasis with amyloid pathology and petition for further investigation into the targeting of this relationship to improve cognitive performance

Chronic, Mild Hypothermic Environmental Temperature does not Ameliorate Cognitive Deficits in an Alzheimer\u27s Disease Mouse.

Metabolic dysfunction increases with age and is a contributing factor to Alzheimer\u27s disease (AD) development. We have previously observed impaired insulin sensitivity and glucose homeostasis in the APP/PS1 model of AD. To improve these parameters, we chronically exposed male and female mice to mild hypothermic environmental temperature (eT), which positively modulates metabolism. Although a hypothermic eT normalized insulin sensitivity, glucose tolerance was still impaired in both sexes of AD mice. We observed increased plasma glucagon and BAFF in both sexes, but additional sexually dimorphic mechanisms may explain the impaired glucose homeostasis in AD mice. Hepatic Glut2 was decreased in female while visceral adipose tissue TNFα was increased in male APP/PS1 mice. A mild hypothermic eT did not improve spatial learning and memory in either sex and increased amyloid plaque burden in male APP/PS1 mice. Overall, plasma markers of glucose homeostasis and AD pathology were worse in female compared to male APP/PS1 mice suggesting a faster disease progression. This could affect therapeutic outcome if interventional strategies are administered at the same chronological age to male and female APP/PS1 mice. Furthermore, this data suggests a dichotomy exists between mechanisms to improve metabolic function and cognitive health that may be further impaired in AD

GLUTAMATERGIC AND METABOLIC DYSREGULATION IN ALZHEIMER\u27S DISEASE MOUSE MODELS: THE IMPACT OF PRODROMAL RILUZOLE TREATMENT

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