Vascular cognitive impairment (VCI) is a heterogeneous entity that has been classically linked with ischemic disease. Furthermore, there is considerable evidence indicating that chronic cerebral hypoperfusion is an early feature of Alzheimer's disease (AD) and cardiovascular risk factors increase the incidence of both vascular cognitive impairment and AD. This has led many to speculate that chronic cerebral hypoperfusion could play important roles both in AD and VCI and could serve as a mechanistic link between these two entities. This proposal will address fundamental questions about the role of cerebral hypoperfusion in the development of age-related cognitive decline. Specifically, it will focus on its effects in the stability of synaptic connections, building up on preliminary observations we have made using time-lapse two-photon microscopy of neuronal structures in living mice. We have observed that dendritic spines the main sites of excitatory synaptic connections undergo remarkable destabilization in the presence of cerebral hypoperfusion in mouse models. This occurs in the absence of stroke, suggesting that hypoperfusion below the threshold for ischemia could be an underestimated mechanism of pathology. This proposal will systematically test mechanisms of neuronal circuit injury in cerebral hypoperfusion, examine their interactions with AD pathology and probe potential therapeutic strategies. Specifically, it will test the hypothesis that chronic cerebral hypoperfusion in the absence of ischemia induces synaptic destabilization and enhances the synaptotoxic effects of A?-amyloid and neuroinflammation eventually leading to neurodegeneration. To test this hypothesis, we will use animal models of global and focal cerebral hypoperfusion, in vivo two-photon microscopy imaging of neuronal structures, amyloid plaques and microglia as well as histological and biochemical methods.
In aim 1, we will further characterize the effects of chronic cerebral hypoperfusion on synaptic stability.
In aim 2, we will examine the effects of chronic cerebral hypoperfusion on A?-amyloid deposition and synaptotoxicity.
In aim 3, we will investigate the role of neuroinflammation in hypoperfusion- induced synaptic disruption. Together, these studies will greatly advance our understanding of complex mechanisms through which CCH interacts with neurons, a-amyloid and microglia eventually leading to neuronal circuit injury and dementia. .

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG027855-04
Application #
7793490
Study Section
Clinical Neuroimmunology and Brain Tumors Study Section (CNBT)
Program Officer
Petanceska, Suzana
Project Start
2007-02-15
Project End
2012-01-31
Budget Start
2010-03-01
Budget End
2011-01-31
Support Year
4
Fiscal Year
2010
Total Cost
$246,121
Indirect Cost
Name
Northwestern University at Chicago
Department
Neurology
Type
Schools of Medicine
DUNS #
005436803
City
Chicago
State
IL
Country
United States
Zip Code
60611
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Condello, Carlo; Yuan, Peng; Schain, Aaron et al. (2015) Microglia constitute a barrier that prevents neurotoxic protofibrillar A?42 hotspots around plaques. Nat Commun 6:6176
Hill, Robert A; Tong, Lei; Yuan, Peng et al. (2015) Regional Blood Flow in the Normal and Ischemic Brain Is Controlled by Arteriolar Smooth Muscle Cell Contractility and Not by Capillary Pericytes. Neuron 87:95-110
Whiteus, Christina; Freitas, Catarina; Grutzendler, Jaime (2014) Perturbed neural activity disrupts cerebral angiogenesis during a postnatal critical period. Nature 505:407-11
Grutzendler, Jaime; Murikinati, Sasidhar; Hiner, Bennett et al. (2014) Angiophagy prevents early embolus washout but recanalizes microvessels through embolus extravasation. Sci Transl Med 6:226ra31
Schain, Aaron J; Hill, Robert A; Grutzendler, Jaime (2014) Label-free in vivo imaging of myelinated axons in health and disease with spectral confocal reflectance microscopy. Nat Med 20:443-9
Hill, Robert A; Patel, Kiran D; Goncalves, Christopher M et al. (2014) Modulation of oligodendrocyte generation during a critical temporal window after NG2 cell division. Nat Neurosci 17:1518-27
Harb, Roa; Whiteus, Christina; Freitas, Catarina et al. (2013) In vivo imaging of cerebral microvascular plasticity from birth to death. J Cereb Blood Flow Metab 33:146-56
Grutzendler, Jaime (2013) Angiophagy: mechanism of microvascular recanalization independent of the fibrinolytic system. Stroke 44:S84-6
Abraham, Jayne; Fox, Patrick D; Condello, Carlo et al. (2012) Minocycline attenuates microglia activation and blocks the long-term epileptogenic effects of early-life seizures. Neurobiol Dis 46:425-30

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