Differential synaptic responses of calcium permeable AMPA receptors in resilient individuals to Alzheimer’s disease neuropathology

Background: Alzheimer's disease (AD) is a common form of dementia characterized by the accumulation of amyloid beta (Aβ) and tau proteins in the brain, leading to disruption of cellular calcium signaling. AMPA receptors (AMPARs) are implicated in this process, with two forms found in the brain — calcium-impermeable (CI-) and calcium-permeable (CP-) AMPARs. However, it is unclear whether the ratio of CI- and CP-AMPARs differs in AD, or whether they have different structures or modifications. In this study, we investigate differences in the synaptic responses of CP-AMPARs in four groups of postmortem human brain tissue: resistant (non-demented/no neuropathology), AD match resistant (age-matched AD individuals), resilient (non-demented with AD neuropathology) and AD match resilient (age-matched AD individuals). Method: We isolated synaptic membranes from the parietal cortex of 7 resistant (3M, 4F), 7 AD match resistant (2M, 2F), 8 resilient (2M, 6F) and 7 AD match resilient (2M, 5F) individuals, and microtransplanted the membranes into Xenopus laevis oocytes. We activated all AMPARs with the agonist kainate and then inhibited kainate by applying IEM-1460 to identify how many CP-AMPARs contributed to the original kainate activation. The responses were recorded using two-electrode voltage clamp technique. A total of 6-12 oocytes from 4-5 frogs were recorded to ensure robust results. Data analysis was performed using JMP Pro 16 and two-tailed unpaired Student's t test was used for simple comparisons, with a significance level set at p < 0.05. Result: Our findings suggest that there are alterations in the permeability or efficacy of CP-AMPARs in resilient individuals compared to age-matched AD individuals, as demonstrated by differences in the response to IEM-1460. These alterations may be related to structural or signaling changes, as suggested by previous proteomic analyses. Further studies are necessary to fully understand the underlying mechanisms and implications for AD progression. Conclusion: Our study sheds light on the potential role of CP-AMPARs in AD pathology and resilience. This provides a foundation for future research to explore the mechanisms of CP-AMPAR alterations in AD and may offer insights into novel therapeutic approaches.