Age-related decrease in stimulated glutamate release and vesicular glutamate transporters in APP/PS1 transgenic and...

Area of Science:

• Neuroscience
• Neurobiology
• Alzheimer's Disease Research

Background:

• Alzheimer's disease (AD) is characterized by amyloid pathology and cognitive decline.
• Glutamatergic neurotransmission plays a critical role in memory and synaptic plasticity.
• Dysregulation of glutamate release is implicated in AD pathogenesis.

Purpose of the Study:

• To investigate age-dependent changes in glutamate release in APdE9 mice, an AD model.
• To assess the relationship between glutamate release, spatial memory, and amyloid pathology.
• To examine alterations in glutamate transporters and astrocyte activation in APdE9 mice.

Main Methods:

• Microdialysis was used to measure baseline and KCl-stimulated glutamate release in freely moving young adult and middle-aged APdE9 mice and wild-type littermates.
• Spatial memory was assessed using the water maze task.
• Levels of glutamate transporters (VGLUT1, VGLUT2, GLT-1) and synaptophysin were analyzed.
• Astrocyte activation was measured by glial acidic fibrillary protein (GFAP) expression.

Main Results:

• APdE9 mice demonstrated progressive spatial memory impairment from 6 to 15 months of age.
• Stimulated glutamate release significantly declined in middle-aged (17 months) APdE9 mice compared to young adults (7 months).
• Aged wild-type mice showed increased glutamate release upon stimulation, whereas aged APdE9 mice did not exhibit this response.
• An age-dependent decrease in VGLUT1 levels was observed, alongside increased astrocyte activation in middle-aged APdE9 mice.

Conclusions:

• Blunted pre-synaptic glutamate release response in APdE9 mice correlates with spatial memory deficits.
• Age-dependent alterations in glutamatergic neurotransmission are exacerbated in the APdE9 mouse model of AD.
• These findings suggest that impaired glutamate release contributes to cognitive decline in Alzheimer's disease.