Memory loss is one of the earliest clinical symptoms of Alzheimer's disease (AD), the most common neurodegenerative disease, which is influenced by numerous biological factors, including aging and sex. Pathologically, AD is characterized by the accumulation of β-amyloid (Aβ) peptides into plaques, and intracellular aggregates of hyperphosphorylated tau protein in neurofibrillary tangles (NFTs). Both pathologies are accompanied by synaptic loss, inflammation, and early functional disruptions in excitatory and inhibitory neurons in hippocampal memory circuits. How Aβ and tau differentially affect excitatory and inhibitory hippocampal neurons causing memory deficits during aging and depending or not on sex remains largely unknown. In this doctoral thesis, I studied the effect of early Aβ and tau pathologies on excitatory (CaMKIIα) and inhibitory Parvalbumin (PV) hippocampal neurons in a novel AD mouse model that expresses both mutant human APP and MAPT/Tau genes (APP/Tau mice). The results show that early hippocampal-dependent spatial learning and memory deficits in 6-month-old male and female Tau and APP/Tau mice coincide with hippocampal synaptic tau accumulation, loss of excitatory synaptic integrity, and accumulation of Aβ and tau in hippocampal glutamatergic neurons, but not PV interneurons. Bulk RNA-seq analyses revealed specific downregulation of synaptic genes in the hippocampus of male and female Tau and APP/Tau mice, as well as genotype and sex-dependent changes in gene expression affecting inflammation, autophagy, myelination and neuronal excitability pathways. Cell type-specific mRNA-seq in APP/Tau;RiboTag mice showed transcriptional alterations of metabolic and synaptic genes in hippocampal CaMKIIα+ neurons of APP/Tau mice. Interestingly, hippocampal PV expressing inhibitory neurons undergo sex-specific reduced density, disrupted morphology and transcriptional alterations (including synaptic and axon maintenance related genes) in APP/Tau mice, despite absence of Aβ and tau accumulation in these cells, suggesting that excitatory-expressed Aβ and tau exert cell non-autonomous effects in PV neurons. Finally, cell-type specific RNA-seq allowed us to identify the distinct gene programs induced by learning and memory in glutamatergic (mRNA processing and synaptic transmission) and PV inhibitory (ATP metabolism, ion channel activity synaptic transmission) neurons in our model. In conclusion, this doctoral thesis has studied the translatomes of hippocampal excitatory and inhibitory neurons in male and female animals of a novel AD model that recapitulates Aβ and tau pathologies, unveiling, for the first time, not only the specific effects of each pathology but also the influence of sex on these cell type-specific alterations.
Neuron-type molecular pathways underlying hippocampal-dependent memory deficits in Alzheimer's disease transgenic mice
Deprada Fernández, Á. (Author). 20 Nov 2024
Student thesis: Doctoral thesis
Student thesis: Doctoral thesis