Thermotherapy has Sexually Dimorphic Responses in APP/PS1 Mice.

A thermoregulatory decline occurs with age due to changes in muscle mass, vasoconstriction, and metabolism that lowers core body temperature (Tc). Although lower Tc is a biomarker of successful aging, we have previously shown this worsens cognitive performance in the APP/PS1 mouse model of Alzheimer's disease (AD) [1]. We hypothesized that elevating Tc with thermotherapy would improve metabolism and cognition in APP/PS1 mice. From 6-12 months of age, male and female APP/PS1 and C57BL/6 mice were chronically housed at 23 or 30°C. At 12 months of age, mice were assayed for insulin sensitivity, glucose tolerance, and spatial cognition. Plasma, hippocampal, and peripheral (adipose, hepatic, and skeletal muscle) samples were procured postmortem and tissue-specific markers of amyloid accumulation, metabolism, and inflammation were assayed. Chronic 30°C exposure increased Tc in all groups except female APP/PS1 mice. All mice receiving thermotherapy had either improved glucose tolerance or insulin sensitivity, but the underlying processes responsible for these effects varied across sexes. In males, glucose regulation was influenced predominantly by hormonal signaling in plasma and skeletal muscle glucose transporter 4 expression, whereas in females, this was modulated at the tissue level. Thermotherapy improved spatial navigation in male C57BL/6 and APP/PS1 mice, with the later attributed to reduced hippocampal soluble amyloid-ß (Aß)42. Female APP/PS1 mice exhibited worse spatial memory recall after chronic thermotherapy. Together, the data highlights the metabolic benefits of passive thermotherapy with potential nonpharmacological management for some individuals with AD, and provides further evidence for the necessity of adopting personalized patient care.

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

BACKGROUND: 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-ß (Aß) 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 (AßPP/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's Disease Mouse.

Metabolic dysfunction increases with age and is a contributing factor to Alzheimer's 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 B-cell activating factor in both sexes, but additional sexually dimorphic mechanisms may explain the impaired glucose homeostasis in AD mice. Hepatic Glut2 was decreased in females 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 females compared to male APP/PS1 mice suggesting a faster disease progression. This could affect the therapeutic outcomes 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.

Amyloid-ß42 stimulated hippocampal lactate release is coupled to glutamate uptake.

Since brain glucose hypometabolism is a feature of Alzheimer's disease (AD) progression, lactate utilization as an energy source may become critical to maintaining central bioenergetics. We have previously shown that soluble amyloid-ß (Aß)42 stimulates glutamate release through the α7 nicotinic acetylcholine receptor (α7nAChR) and hippocampal glutamate levels are elevated in the APP/PS1 mouse model of AD. Accordingly, we hypothesized that increased glutamate clearance contributes to elevated extracellular lactate levels through activation of the astrocyte neuron lactate shuttle (ANLS). We utilized an enzyme-based microelectrode array (MEA) selective for measuring basal and phasic extracellular hippocampal lactate in male and female C57BL/6J mice. Although basal lactate was similar, transient lactate release varied across hippocampal subregions with the CA1 > CA3 > dentate for both sexes. Local application of Aß42 stimulated lactate release throughout the hippocampus of male mice, but was localized to the CA1 of female mice. Coapplication with a nonselective glutamate or lactate transport inhibitor blocked these responses. Expression levels of SLC16A1, lactate dehydrogenase (LDH) A, and B were elevated in female mice which may indicate compensatory mechanisms to upregulate lactate production, transport, and utilization. Enhancement of the ANLS by Aß42-stimulated glutamate release during AD progression may contribute to bioenergetic dysfunction in AD.

Hippocampal alterations in glutamatergic signaling during amyloid progression in AßPP/PS1 mice.

Our previous research demonstrated that soluble amyloid-ß (Aß)42, elicits presynaptic glutamate release. We hypothesized that accumulation and deposition of Aß 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 AßPP/PS1 and age-matched C57BL/6J control mice. Starting at 6 months of age, AßPP/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 AßPP/PS1 mice. However, CA1 evoked glutamate release in AßPP/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.