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

Abstract

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 agematched 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.

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

“…(2-4 months old) AβPP/PS1 mice without detectable changes in basal glutamate levels (Hascup et al, 2020), and soluble Aβ 42 , which is one of the earliest detectable biomarkers of AD (Jack et al, 2013), elicits glutamate release . More recently, we determined that both evoked glutamate release and basal glutamate levels were elevated throughout the hippocampus by 12 months of age (Hascup et al, 2019).…”

“…To slow or stop AD progression, it may be necessary to target neurological components that are altered during the prodromal phase of AD. Increasing evidence supports the glutamatergic system as a possible early target that meets these criteria (Hascup et al, 2019(Hascup et al, , 2020Minkeviciene et al, 2008;Paula-Lima et al, 2013).…”

“…Alterations to glutamate release and clearance may lead to the cognitive and functional decline observed in AD (Hascup et al, 2019(Hascup et al, , 2020Hunsberger et al, 2015;Miller et al, 2008;O'Brien et al, 2010). A prevailing hypothesis in AD research supports persistent, excessive activation of NMDA receptors impedes the detection of physiological signals and initiating cognitive impairment (Olney et al, 1997;Parameshwaran et al, 2008;Parsons et al, 2007;Talantova et al, 2013;Winblad & Poritis, 1999).…”

“…Furthermore, we have also reported subregion and age specific alterations in hippocampal glutamatergic activity in AβPP/PS1. Elevated dentate (DG) and CA1 evoked glutamate release is observed at 2-4 months of age, while elevated basal glutamate in observed in these regions by 6 months of age (Hascup et al, 2020). These elevated levels continue to 12 months of age (Hascup et al, 2018(Hascup et al, , 2019, when cognitive deficits are more pronounced.…”

Amyloid-β42 Stimulated Hippocampal Lactate Release is Coupled to Glutamate Uptake

“…As AD progresses soluble Aβ42 concentrations increase leading to persistent activation of these receptors that chronically elevate extracellular glutamate levels (Hascup et al 2020b) contributing to cognitive and functional decline (Danysz and Parsons 2012).…”