Rearrangement of AMPA receptors in non-demented individuals with high pathology of Alzheimer's disease

Background: Alzheimer’s disease (AD) is the most common form of dementia in the ageing population. The diagnosis is made at the clinical level since the definitive diagnosis requires a brain biopsy to confirm the presence of amyloid beta and hyperphosphorylated tau protein aggregates. Stunningly, histopathologic findings of AD have been found on postmortem brain tissue of individuals who did not develop dementia throughout their lifetime — non-demented with high pathology (NDAN). We propose that postsynaptic receptors in NDAN individuals, such as AMPA receptors, have a different structure and function that confers them protection from the effects of amyloid beta and possibly tau oligomers (e.g., disruption of calcium homeostasis) that lead to the clinical symptoms of dementia.
Methods: To determine whether there is a difference in the structure and function of AMPA receptors, we analyzed the proteomic and transcriptomic data of 30 individuals: 7 controls (absence of AD histopathologic findings; 3 males and 4 females), 15 AD (7 males and 8 females), and 8 NDAN (2 males and 6 females). From the three groups, we obtained the fractional contribution of each AMPA receptor subunit, performed correlation analyses within the subunits to predict the stoichiometry of the receptor, and ran a gene ontology analysis from the most significant genes that interacted with the AMPAR subunits.
Results: The proteomic and transcriptomic data showed changes in the expression, organization, and synaptic remodeling of AMPA receptors in control, AD and NDAN individuals. AMPA receptors in the three groups participate in neuronal and synaptic signaling pathways, however NDAN individuals additionally show a very robust participation in cellular respiration pathways, indicating that there is a strong compensatory process and better integration of synaptic function and mitochondrial energy management in these individuals.
Conclusions: We found differences at the structural and functional level of postsynaptic receptors in control, AD, and NDAN individuals. The AMPA receptor remodeling and compensatory cellular respiratory pathways in NDAN individuals may contribute to block the disruption of intracellular calcium homeostasis and synaptic transmission produced by amyloid beta oligomers; all these preventing NDAN individuals from developing cognitive impairment.