Excitatory and inhibitory synaptic differences in Alzheimer’s disease progression in MTG neuronal cells, a RNAseq single cell analysis.

Alzheimer’s disease (AD) is a neurodegenerative disorder and the main cause of dementia worldwide. Synaptic dysfunction in the middle temporal gyrus (MTG), an area involved in language and memory, has been associated with main behavioral symptoms. Our group has previously described that regional disturbances in excitatory (E) and inhibitory (I) synapses may contribute to disease progression. However, it is not known which cell types are major drivers of E/I imbalances in the MTG.
We hypothesize that vulnerable cell types present E/I imbalance as measured by the ratio of gene expression of excitatory and inhibitory postsynaptic proteins and their corresponding receptors. Thus, we used single cell RNAseq data from human MTG provided by the Seattle Alzheimer’s Disease Brain atlas (SEA-AD), to investigate the differences in across disease stages of AD patients along the different neuronal subclusters.
We will present our findings describing differential changes of E/I ratio depending on the cell type and their supertypes. Interestingly, non-neuronal cells expressed postsynaptic receptors that change with disease progression. We also observed differential changes in the E/I ratio of excitatory and inhibitory that may correlate with the hyper- and hypoexcitability that has been observed in AD. In the case of somatostatin cell types which are more vulnerable to AD stages, we observed a general decrease in the E/I ratio in highly affected donors, with some exception in specific supertypes. These cells are responsible to exert their inhibitory effects over excitatory neurons. The increase in the inhibitory component at later stages would reduce their neuronal firing, contributing to an increase of excitability in the brain circuit.
Thus, differences at the transcriptomic level in synapsis present useful information of the disease progression setting the basis to identify AD in early stages.