Altered glutamate dynamics in a mouse model of Alzheimer’s disease: Novel early biomarkers with therapeutic potential

Michael Smith Foundation for Health Research/The Pacific Alzheimer Research Foundation Post-Doctoral Fellowship Award

 

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder. With no cure available, it imposes a major burden on society. In AD, a protein called amyloid beta accumulates into plaques in the brain. This event is an early and predictive marker for AD and can be detected up to 20 years before clinical symptoms arise.

 

We are exploring the dysfunction and hyperactivity of various cell types in the presence of amyloid plaques. We will investigate the possible role of altered glutamate dynamics in mouse models of AD. Fluorescent labelling will shed light on changes in glutamate signalling in awake and behaving AD mice. We will also test whether Ceftriaxone can restore normal glutamate dynamics in these mice.

 

Ultimately, our work with AD mouse models and novel glutamate imaging could shed light on possible drug targets and enable early intervention for people with Alzheimer’s disease.

End of Award Update

Source: CLEAR Foundation

 

What did we learn?

During our study it became clear that amyloid deposits have a drastic impact on glutamate signaling. This early cellular signaling deficit was only visible using in vivo 2-Photon imaging and a region-specific analysis of real time glutamate transients in direct proximity to amyloid plaques. We found areas of chronically high glutamate levels directly surrounding amyloid plaques and adjacent areas in which glutamate signaling was impaired. In larger scale wide-field real-time imaging experiments this effect was lost, indicating the importance of region-specific effects on cellular function in the early stages of the disease. Moreover, we used luminescent conjucated oligothiophens (provided by Dr. Peter Nilson, Linköping University) to visualize prefibrillary forms of amyloid. We found a direct overlap of these prefibrillary forms of amyloid surrounding the dense core plaque and a decrease in astrocytic GLT-1 transporter. We hypothesized that this decrease in GLT-1 is responsible for the observed glutamate dysfunction that was found in our experiments using stimulation experiments in awake and anesthetized animals. We thus used Ceftriaxone to restore GLT-1 expression in our mouse model of AD. We provided longitudinal imaging data of glutamate transients before and after Ceftriaxone treatment and could show that this partially restores glutamate signaling.

 

Why is this knowledge important?

As prefibrillary species are present in the brain before dense core plaques are formed it is important to further our understanding of their impact on cellular function. Moreover, it is essential to develop strategies that aim at the earlies stage that amyloids have on cellular function as these can be treated. Once neurons and other cells undergo cell death, strategies of recovery are much harder to implement. Our results provided a new therapeutical target that not only treats the disease on a symptomatic level but in an amyloid centric way that prevents/delays cellular dysfunction at an early stage in the disease.

 

What are the next steps?

We are currently expanding our research to investigate the impact of prefibrillary amyloid species on vessel function to search for more potential therapeutic targets.

 

Publications