Cerebral microvascular occlusion and/or chronic global cerebral hypoperfusion when coexistent with Alzheimer’s disease can affect the dynamics of amyloid deposition as well as microglia clustering and activation around amyloid plaques, resulting in synergistic effects on the progression of neuronal circuit disruption.
The overall goal of this proposal is to improve our understanding of the role vascular factors play in the development and progression of age-related cognitive decline and their contribution to AD neuropathology. In addition, we aim to improve our understanding of the complex interactions that take place between blood vessels, neurons, microglia, and amyloid deposits. For this purpose, we will develop and improve methods to study at high temporal and spatial resolution the dynamics of cell-cell interactions in the living mouse brain by means of transcranial in vivo two-photon microscopy (TPM). Our specific aims are:
1. Characterize the patterns of synaptic turnover and disruption in mouse models of microvascularocclusion and chronic global cerebral hypoperfusion.
2. Determine the effects of cerebral hypoperfusion on the turnover and accumulation of ß-amyloid plaques and the role of microglia clustering in synaptic disruption.
We have crossbred a transgenic mouse model of AD with mice that express various fluorophores in subset of cortical pyramidal neurons and microglia. This triple transgenic mice with multicolor labeling will be used to obtain time-lapse images of amyloid plaques, microglia, and neurons. Mice will be subjected to several models of chronic cerebral hypoperfusion, carotid embolization, and photothrombosis. Plaque turnover, microglia migration towards plaques and microglia neuron and plaque-neuron interaction will be studied dynamically in living mice by means of transcranial two-photon microscopy over intervals ranging from hours to months. A subset of experiments will use Lentiviral vectors driving the expression of red fluorescent protein in cortical neurons to study these interactions.