Front Neurosci: Role of acute exposure to Aβ on glutamatergic system

Glutamate is the main excitatory transmitter of the central nervous system and plays a vital role
in the normal function and excitability of neural networks.
It acts on a variety of receptors, roughly divided into ionic types (including NMDAR, AMPAR, etc.
) and metabolic types
.
Ionic receptors are mainly found on the postsynaptic membrane, while metabolic receptors are found to be expressed
in both neurons and glial cells.
Differential spatial localization of these two receptor isotypes may promote differential activation of receptors, proportional to the amount of glutamate released from the presynaptic space
.
Vesicle glutamate receptors (VGluTs), divided into VGluT1 and VGluT2, are present in presynaptic neurons and are essential
for maintaining vesicular glutamate concentrations.

Studies have shown an association between glutamatergic dysfunction and Aβ exposure, which is associated
with endocytosis of NMDAR and AMPAR.
In this study, we observed the effect of Aβ protein injection on glutamate receptor and transporter expression in specific regions of the hippocampus of mice, quantified the changes in glutamatergic system components, and observed the behavioral response
of animals after acute exposure to Aβ.

Expression of AMPA receptor subunits after 3 days of 1Aβ injection

Unlike previous studies, three days after injection of Aβ1–42, no significant changes were
seen in the expression of the two major subunits of AMPA receptors (GluA1 and GluA2) in the three regions of the mouse hippocampus.
Based on this, the researchers proposed another possible role of Aβ in the acute environment: in the early stages of the disease, Aβ can stabilize and increase the expression of synaptic site GluA1 receptor sub-expression
by enhancing and interacting with intrinsic molecules such as CaMKII and PKA.
A rapid increase in AMPAR expression may be a manifestation of a transient acute response to neurotoxic exposure, followed by a secondary chronic phase that leads to decreased
AMPAR surface expression through a range of Aβ-driving mechanisms, including but not limited to ubiquitination, dephosphorylation, and endocytosis.

Figure 1.
Expression of hippocampal GluA1 in mice after 3 days of Aβ1-42 injection

Expression of NMDA receptor subunits after 3 days of 2Aβ injection

After 3 days of Aβ injection, the expression level of GluN1 receptor subunit increased to varying degrees (especially at different levels of CA3 region).

In addition, expression changes
were observed in mice injected with ACSF compared to NC mice.
Similar to the results observed in the AMPAR subunit, however, most of the latest literature suggests that the main inhibitory effect of Aβ is the effect on synaptic activity, as well as the ubiquitination and internalization
of NMDAR.
The NMDAR GluN1 subunit is an important component of all functional NMDARs, so its expression degree may be representative of the number of
NMDARs at synaptic sites.

Figure 2.
Expression of hippocampal GluN1 in mice after 3 days of Aβ1-42 injection

Expression of vesicle glutamate transporter after 3 days of 3Aβ injection

Only small changes in the expression of VGluT1 and VGluT2 transporters in the mouse hippocampus illustrate the robustness of the vesicle glutamate transport system, and the authors speculate that changes in vesicular glutamate transporters noted by other studies may be the result of
prolonged exposure to Aβ.

4Aβ1-42-induced cognitive changes

Furthermore, in the Y-maze test, mice injected with Aβ1–42 in the lateral ventricles showed significant spatial memory impairment but no significant nonspatial memory deficits, consistent with previous findings in transgenic AD mouse models that showed such impairment
only after long-term exposure to Aβ.

Figure 3.
New object recognition test results

5 Summary

This study provides evidence
of acute and focal effects of Aβ1–42 on hippocampal memory function and glutamatergic system component expression in mice.
Importantly, although glutamatergic systems are relatively resistant to early Aβ1–42-induced neurotoxicity, even small changes in the expression of specific receptor subunits and transporters can lead to significant pathophysiological outcomes
.
Therefore, it is still worth continuing to study how glutamatergic responds to
Aβ stimulation.

Assessing gene expression or other markers associated with glutamatergic signaling, such as postsynaptic density protein, may be the focus of future research to deepen the understanding of Aβ protein-induced glutamatergic alterations and to provide more information
about the disease mechanisms that cause cognitive deficits.