Recently, cerebral microvessel disease has been identified as an important component of Alzheimer's disease. The mechanism of interaction between the diseases is still unclear in part because animal models of microvascular disease are lacking. The proposed work studies the interrelationship between microvascular damage and the accumulation of Ap, the dominant characteristic of Alzheimer's disease. This work builds on the clinical observation that the severity of dementia in Alzheimer's disease is often related to the presence of vascular disease. We use novel optical tools to induce microvascular lesions in transgenic mouse models of Alzheimer's disease and then image the progression of the resulting pathology. Our lesioning technique, femtosecond laser ablation, can disrupt individual microvessels as deep as 500 pm beneath the cortical surface. The study includes multiple types of microvascular lesions, including hemorrhages, ischemic occlusions and transient leakages, all of which potentially contribute to disease progression. Two-photon excited fluorescence microscopy is used to image amyloid plaque development and to measure blood flow and leakage in the microvasculature. This allows time-lapsed study of both the microvascular lesion and amyloid plaque. Post-mortem labeling with A(3 antibodies will be used to further elucidate the impact of the microvascular lesion on Ap accumulation.
In Aim 1, we test whether microvascular clots and hemorrhages trigger rapid amyloid plaque formation at different locations in the vascular tree.
In Aim 2, we ask if vascular lesions earlier in life can induce a predisposition to plaques later. In the final aim, we determine where plaques that are seeded by vascular lesions are relative to different cell types and determine whether inflammation or reactive oxygen species are factors through colocalization studies. In addition, we use histological and immunohistological assays to identify the affected cells and map the Ap accumulation. Our preliminary findings predict that the presence of a microvascular clot will accelerate the local deposition of Ap plaques. These data suggest that microvascular lesions could play an important role in Alzheimer's disease pathogenesis. Relevance ~ Alzheimer's disease is the most common cause of dementia in the elderly. Clinically, Alzheimer's disease is often entangled with vascular disease, suggesting that the two diseases are intimately interrelated. In many patients, sucessful treatment will have to address both aspects. This work investigates how the two conditions might worsen each other and will help identify strategies for preventing dementia.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Postdoctoral Individual National Research Service Award (F32)
Project #
4F32AG031620-03
Application #
8140740
Study Section
Special Emphasis Panel (ZRG1-F01-E (20))
Program Officer
Petanceska, Suzana
Project Start
2010-02-14
Project End
2013-02-13
Budget Start
2012-02-14
Budget End
2013-02-13
Support Year
3
Fiscal Year
2012
Total Cost
$57,734
Indirect Cost
Name
Cornell University
Department
Engineering (All Types)
Type
Schools of Engineering
DUNS #
872612445
City
Ithaca
State
NY
Country
United States
Zip Code
14850
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Nishimura, Nozomi; Schaffer, Chris B (2013) Big effects from tiny vessels: imaging the impact of microvascular clots and hemorrhages on the brain. Stroke 44:S90-2
Shih, Andy Y; Driscoll, Jonathan D; Drew, Patrick J et al. (2012) Two-photon microscopy as a tool to study blood flow and neurovascular coupling in the rodent brain. J Cereb Blood Flow Metab 32:1277-309
Santisakultarm, Thom P; Cornelius, Nathan R; Nishimura, Nozomi et al. (2012) In vivo two-photon excited fluorescence microscopy reveals cardiac- and respiration-dependent pulsatile blood flow in cortical blood vessels in mice. Am J Physiol Heart Circ Physiol 302:H1367-77
Huynh, John; Nishimura, Nozomi; Rana, Kuldeepsinh et al. (2011) Age-related intimal stiffening enhances endothelial permeability and leukocyte transmigration. Sci Transl Med 3:112ra122
Rosidi, Nathanael L; Zhou, Joan; Pattanaik, Sanket et al. (2011) Cortical microhemorrhages cause local inflammation but do not trigger widespread dendrite degeneration. PLoS One 6:e26612
Nguyen, John; Nishimura, Nozomi; Fetcho, Robert N et al. (2011) Occlusion of cortical ascending venules causes blood flow decreases, reversals in flow direction, and vessel dilation in upstream capillaries. J Cereb Blood Flow Metab 31:2243-54