Vulnerability of hippocampal synaptic plasticity and adult neurogenesis in Alzheimer's disease

Alzheimer's disease (AD) is a highly common neurodegenerative disorder, for which no disease-modifying treatment exists today. Pathological synaptic changes, most likely caused by soluble forms of the pathological proteins Aβ and tau and their interactions, are central and early events in AD. Synaptic dysfunction, altered neural network activity and a dramatic degeneration of neurons in important brain regions ultimately lead to dementia and other symptoms. In this thesis, we investigated synaptic function across multiple brain regions and hippocampal subregions in relevant mouse models for AD, using in vitro electrophysiology in brain slices. We started with control mice and found large regional differences, with much higher potentiation levels in the DG of ventral than dorsal slices. This was reflected in a specific ventral DG-deficit in AD mice, while they showed a specific dorsal deficit in the CA1 region. We also assessed regional effects on adult hippocampal neurogenesis and found that generally more new cells were generated in the ventral hippocampus, but the process appeared not to be affected in our AD models. Taken together, our results confirm that amyloid and tau pathology can independently exert synaptotoxic effects. This does not fully support the prevailing amyloid cascade hypothesis, in which amyloid drives and aggravates tau pathology. We also corroborate the sensitivity of LTP to detect early pathological changes caused by amyloid and/or tau in mouse models, long before the onset of plaques, tangles and severe behavioral symptoms. Finally, our results provide additional evidence that the subfields and dorsoventral segments of the hippocampus have different synaptic properties and vulnerabilities to disease, and that they should be clearly distinguished. Overall, the most plastic subregions appeared the most vulnerable to AD pathology. Provided that our findings in the murine hippocampus can be successfully translated to humans with AD, further defining which regions are the earliest affected and most vulnerable will be crucial for the development of preventive and therapeutic interventions, especially those based on the targeted neuromodulation of affected circuits.status: publishe