Neuro-Immune Interactions in the Vascular/Alzheimer's Dementia Complex

Jaime Grutzendler, M.D.

Northwestern University Feinberg School of Medicine

Funded in June, 2005: $200000 for 3 years
LAY SUMMARY . ABSTRACT . BIOGRAPHY . HYPOTHESIS .

ABSTRACT

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Neuro-Immune Interactions in the Vascular/Alzheimer's Dementia Complex

Alzheimer's disease (AD) is the most common cause of cognitive decline in the elderly. However, increasing evidence suggests that cerebro-vascular disease (CVD) frequently coexists with classical AD pathology, while many risk factors for CVD overlap with those for AD. Furthermore, blood flow studies have demonstrated cerebral hypoperfusion even in presymptomatic stages of AD. This has led many to suggest that AD and CVD share common pathophysiological mechanisms mediated by poorly understood interactions between neurons, amyloid deposits, glial cells, and blood vessels. Recently, we have developed methods for using in vivo two-photon microscopy of the mouse brain to study changes in the dynamic properties of dendritic spines in aging and in AD.

Our initial observations provide an important foundation to explore in the living mouse brain complex cellular interactions taking place at the interface between CVD and AD. Newly developed methods of focal microvascular occlusion or chronic global cerebral hypoperfusion will be used in mouse models of AD to study the role of CVD in modulating the temporal and spatial evolution of amyloid plaque deposition. We will explore whether CVD can induce changes in synaptic stability in the absence of overt stroke and whether CVD and AD act in a synergistic fashion to disrupt neuronal circuits. Finally, by obtaining high resolution dynamic images of the interaction between amyloid plaques, microglia and dendrites in vivo, we will determine if microglia play a direct role in destabilizing synapses in CVD and AD. By greatly enhancing our understanding of the interactions between vascular factors, neuroinflammation and AD pathology in vivo, these studies we hope, will suggest possible cellular processes where therapeutic intervention could alter the course of neuronal circuit disruption and dementia. In addition, they will determine the importance of prevention and early intervention of CVD as an approach to delay the onset and progression of cognitive decline.

INVESTIGATOR BIOGRAPHIES

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Jaime Grutzendler, M.D.

Assistant Professor of Neurology, Northwestern University

HYPOTHESIS

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Hypothesis:
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.

Goals:
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.

Methods:
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.