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 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.
Highlights
Our previous research demonstrated that soluble amyloid-β (Aβ)[42], elicits presynaptic glutamate release
Hippocampal hyperactivation during a memory encoding task was observed a decade before cognitive decline in a cohort of individuals with the presenilin 1 (PS1) E280A mutation that is associated with early onset A D8
A 3-year longitudinal study showed that elevated hippocampal activity was present in plaque positive mild cognitive impairment (MCI) patients who subsequently showed faster progression of cognitive decline compared to MCI patients without plaque a ccumulation[9]
Summary
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 [2,3,4, 6,7,8], and [18,19,20] month-old male AβPP/PS1 and agematched C57BL/6J control mice. Plaque deposition was anatomically aligned (but temporally delayed) with elevated glutamate levels; whereby accumulation was first observed in the CA1 and DG starting at [6,7,8] months that progressed throughout all hippocampal subregions by [18,19,20] months of age. These studies support that aberrant hippocampal neuronal activity precedes clinical AD diagnosis and suggests elevated glutamatergic signaling as the driving force associated with disease p rogression[12,13]
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