Abstract
Alzheimer’s disease (AD) is the leading type of dementia worldwide. Despite an increasing burden of disease due to a rapidly aging population, there is still a lack of complete understanding of the precise pathological mechanisms which drive its progression. Glutamate is the main excitatory neurotransmitter in the brain and plays an essential role in the normal function and excitability of neuronal networks. While previous studies have shown alterations in the function of the glutamatergic system in AD, the underlying etiology of beta amyloid (Aβ1–42) induced changes has not been explored. Here we have investigated the acute effects of stereotaxic hippocampal Aβ1–42 injection on specific glutamatergic receptors and transporters in the mouse hippocampus, using immunohistochemistry and confocal microscopy 3 days after Aβ1–42 injection in aged male C57BL/6 mice, before the onset of neuronal cell death. We show that acute injection of Aβ1–42 is sufficient to induce cognitive deficits 3 days post-injection. We also report no significant changes in glutamate receptor subunits GluA1, GluA2, VGluT1, and VGluT2 in response to acute injection of Aβ1–42 when compared with the ACSF-vehicle injected mice. However, we observed increased expression in the DG hilus and ventral stratum (str.) granulosum, CA3 str. radiatum and str. oriens, and CA1 str. radiatum of the GluN1 subunit, and increased expression within the CA3 str. radiatum and decreased expression within the DG str. granulosum of the GluN2A subunit in Aβ1–42 injected mice compared to NC, and a similar trend observed when compared to ACSF-injected mice. We also observed alterations in expression patterns of glutamatergic receptor subunits and transporters within specific layers of hippocampal subregions in response to a microinjection stimulus. These findings indicate that the pathological alterations in the glutamatergic system observed in AD are likely to be partially a result of both acute and chronic exposure to Aβ1–42 and implies a much more complex circuit mechanism associated with glutamatergic dysfunction than simply glutamate-mediated excitotoxic neuronal death.
Highlights
Beta amyloid (Aβ) is a ∼4 kDa peptide product derived from the cleavage of amyloid precursor protein (APP)
The GluA1 receptor subunit displayed diffuse staining within the str. radiatum and str. oriens, with marked immunoreactivity localized to cellular processes within the str. pyramidale of the CA3 (Figure 2)
Glutamatergic dysfunction has been reported in chronic neurodegenerative conditions such as Alzheimer’s disease (AD), the precise effect Aβ has within the hippocampal environment is not well-understood
Summary
Beta amyloid (Aβ) is a ∼4 kDa peptide product derived from the cleavage of amyloid precursor protein (APP). The APP molecule can be cleaved by two different secretases; cleavage by alpha and gamma secretase yields nonneurotoxic fragments (Sadigh-Eteghad et al, 2015), while Aβ is generated from the cleavage of APP through the beta and gamma secretase pathway (Selkoe, 1998). This Aβ can further aggregate into larger polymeric structures, including oligomers, protofibrils, and amyloid fibrils, each of which exhibit different functional properties (Finder and Glockshuber, 2007). There is contention as to which form of Aβ is responsible for the pathophysiological responses seen in AD, current data point toward smaller soluble Aβ oligomers as playing the most critical role, with amyloid plaques contributing to but not essential in the pathogenesis of AD (Sakono and Zako, 2010)
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