Hippocampal interneuron alterations in mouse models of familial and sporadic Alzheimer's disease

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder characterized not only by amyloid beta (Aβ) plaques and tau tangles, but also by early disturbances in neuronal network activity. Increasing evidence from human and experimental studies indicates that inhibitory interneurons, which maintain the balance between excitation and inhibition in cortical and hippocampal circuits, are particularly vulnerable in AD. In addition, synaptic alterations are widely reported and have been linked to cognitive decline. This thesis builds on these observations and provides new insights into the mechanisms that shape the early development and progression of AD, highlighting age-dependent disturbances in hippocampal circuits in familial and sporadic forms of the disease at the molecular, cellular, and network levels. Using the APP/PS1 mouse model of familial AD, we performed electrophysiological recordings to assess the intrinsic firing properties of hippocampal interneurons across disease progression (Chapter 2). We found that somatostatin (SST) interneurons are hyperexcitable both at early and later ages, whereas parvalbumin (PV) interneurons showed a biphasic trajectory, with hyperexcitability at 4 months of age and hypoexcitability at 6 months of age. Notably, this work revealed a potential therapeutic window: early inhibition of SST interneurons not only restored their own excitability but also restored PV interneuron excitability at both early and later ages, suggesting that SST hyperexcitability may be an upstream driver of inhibitory imbalance. Our proteomic analysis in APOE4-targeted replacement (TR) and APOE3-TR mice (Chapter 3) provides novel insights into changes in the proteomic composition of hippocampal synaptosomes induced by APOE4, the greatest genetic risk factor for sporadic AD, highlighting age-dependent shifts in synaptic and mitochondrial protein expression that occur independently of Aβ pathology. At 3 months of age, changes were characterized by an upregulation of synaptic and mitochondrial proteins. At 6 months of age, however, synaptic proteins were primarily downregulated and mitochondrial proteins at the synapse were no longer enriched, suggesting an early, transient, and possibly compensatory response in protein expression driven by APOE4-induced stress. Additionally, our cell type enrichment analysis consistently points to the involvement of GABAergic interneurons in these proteomic alterations, providing a basis for future research into their potential role as modulators of APOE4-related synaptic changes. In addition to our mechanistic and molecular studies in AD models, we also show that commonly used surgical techniques can affect animal welfare in such models by introducing physiological changes that may influence experimental outcomes, and highlight automated monitoring of locomotor activity as a valuable and objective method for assessing post-surgical welfare (Chapter 4). Together, this work shows the multifaceted nature of AD pathology and provides new insights into the role of interneuron dysfunction as an early and potentially tractable contributor to disease progression in both familial and sporadic AD. Rather than focusing exclusively on hallmark pathologies such as Aβ plaques and tau tangles, our findings highlight the importance of addressing neuronal network dysfunction as a key contributor to disease pathology, as well as molecular alterations that may even occur independently of Aβ, particularly during the early stages of the disease. These findings open potential new avenues for therapeutic strategies aimed at restoring E/I balance and synaptic function, with the goal of preserving cognitive function.