Thesis title: Promoting phagocytic microglia reverses Aβ-induced synaptic dysregulation in ex vivo hippocampal slices
Aging of the global population has led to a rapid increase in the incidence of Alzheimer’s disease (AD), a major neurodegenerative disorder characterized by a progressive deterioration of memory performance, cognitive decline, and behavioral alterations.
To date, the lack of progress of anti-amyloid agents, thereby challenging the validity of the amyloid hypothesis, has encouraged researchers to investigate alternative mechanisms in non-neuronal cells, among which microglia represent an attractive target. Microglia, traditionally regarded as innate immune cells in the brain, play a key role in the developing brain and contribute to synaptic remodeling. During the pathogenesis of Alzheimer’s disease microglia are prone to stimulatory factors that lead to their overwhelming activation and unbalanced phenotypic changes including phagocytic capacity alterations induced by amyloid-β (Aβ). In AD microglia internalize large amount of synaptic material which reduce their ability to rapidly respond to brain challenges such as clearance of toxic amyloid thus accelerating the neurodegenerative process. Overall, neuroinflammation and related microglial changes drive the progression of the disease before cognitive impairment, acting upstream to Aβ accumulation.
Therefore, pharmacological modulation of microglial reaction in AD progression may pave the way for a new disease modifying approach. Colony stimulating factor 1-receptor (CSF-1R) is predominantly expressed on microglia and its expression is significantly increased in neurodegenerative diseases, possibly contributing to the aberrant chronic inflammatory microglial response typically seen in this patient population. Cumulative findings have indicated that CSF-1R inhibitors can have beneficial effects in preclinical neurodegenerative disease models.
In this thesis, to test the hypothesis that microglia play a critical role in the development of neurodegenerative diseases, we explored the effects of acute microglial modulation on synaptic plasticity and neurotransmission alteration in ex vivo slices and their potential contribution to hippocampal synaptic changes. In the attempt to restore a physiological synaptic function in in vitro AD model, we sought to investigate the microglial contribution using PLX3397, the selective inhibitor of CSF1R pathway. Furthermore, we have also searched for the underlying mechanisms involved in the interplay between synaptic pathology occurring in AD and microglia.
In summary, our results demonstrate a prominent role of microglia in preserving synaptic homeostasis in experimental AD. A restoration of Aβ-induced LTP and excitatory transmission alterations in hippocampus was demonstrated upon PLX-3397 treatment. Moreover, we have found that PLX-3397 acts directly on microglia inducing a functional change in microglial morphology to promote phagocytic activity. Aβ engulfment is, indeed, promoted by PLX-3397 treatment and, in turn, amyloid accumulation in Aβ slices is reduced by PLX-3397 treatment. Finally, our data demonstrated PLX-3397 selectively promotes microglial phagocytosis of Aβ-damaged glutamatergic terminals.
Thus, our findings show that PLX3397 administration could prevent synaptic transmission and plasticity dysfunction and promote a microglial switch toward a phagocytic phenotype thereby clearing the Aβ loaded glutamatergic synapse. These results suggest that targeting microglia may serve as a novel disease modifying therapeutic option for neurodegenerative diseases, including AD.