Project 2: Microglia as Mediators of Dendritic Spine Loss and Plaque Formation in the AD Brain Project Summary/Abstract Dendritic spine loss is closely associated with cognitive decline in Alzheimer's disease (AD) and other disorders. Identifying the mechanisms and stimuli that lead to spine loss in disease is crucial to developing strategies to reverse or prevent these losses, hopefully leading to improvements in cognition. Concurrent with spine loss, chronic microglial-activation is found in the AD brain and in other disorders. As part of our investigations into inflammation in the pathogenesis of AD, we targeted the colony-stimulating factor 1 receptor (CSF1R), as this regulates the proliferation of microglia. We discovered that microglia are physiologically dependent upon CSF1R signaling and that administration of CSF1R antagonists results in the rapid and continued elimination of virtually all microglia from the CNS. We have used this approach to determine that microglia do play a highly significant role in regulating dendritic spine numbers in the adult brain elimination of microglia for 8 weeks results in a ~35% increase in spine densities in CA1 and layer V cortical neurons. Additionally, electrophysiology reveals robustly increased excitatory synaptic inputs to neurons, showing direct evidence of increased active synapses. As we have shown that microglia play a role in modulating spine and synapses in the adult brain, we now propose that this normal function goes awry in AD, leading to overpruning of synapses and resulting in reduced spine densities and subsequent cognitive decline. Our project proposes 4 linked aims that will utilize human tissue to explore the relationship between microglia and dendritic spine loss, as well as plaque formation, in AD. Firstly, we will conduct thorough correlations between microglial densities and morphologies with spine loss from post-mortem tissues in control, MCI and AD subjects. We will then test our hypothesis using tissue from high-pathology control subjects. We will utilize human fibroblasts from MCI subjects, with either a high number of AD microglial-risk SNPs or a low number, which are converted to pluripotent stem cells via iPS cell technology, and then differentiated into microglia. We will then explore how microglia derived from these MCI patients differ in their abilities to 1) prune dendritic spines and 2) phagocytose and clear A?, correlating these findings with the conversion into AD from our MCI subjects. Critical to our approach, we now have the technology to eliminate all endogenous microglia from the mouse CNS via administration of CSF1R inhibitors and then repopulate the mouse brain by infusing in human IPS- derived microglia. Using this method, we can explore the effects of these cells in an in vivo setting and thus determine the effects of these human-derived microglia on both dendritic spines and on clearance/formation of A? plaques. Through these experiments we will be able to fully study the relationship between human microglia and AD pathology/spine loss in a fashion that has not been previously possible. These results will potentially lead to the development of inhibitors that can eliminate microglia in the AD brain and hence prevent spine loss.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Specialized Center (P50)
Project #
5P50AG016573-19
Application #
9462795
Study Section
Special Emphasis Panel (ZAG1)
Project Start
Project End
Budget Start
2018-04-01
Budget End
2019-03-31
Support Year
19
Fiscal Year
2018
Total Cost
Indirect Cost
Name
University of California Irvine
Department
Type
DUNS #
046705849
City
Irvine
State
CA
Country
United States
Zip Code
92617
Kirson, Noam Y; Scott Andrews, J; Desai, Urvi et al. (2018) Patient Characteristics and Outcomes Associated with Receiving an Earlier Versus Later Diagnosis of Probable Alzheimer's Disease. J Alzheimers Dis 61:295-307
Kamara, Dennis M; Gangishetti, Umesh; Gearing, Marla et al. (2018) Cerebral Amyloid Angiopathy: Similarity in African-Americans and Caucasians with Alzheimer's Disease. J Alzheimers Dis 62:1815-1826
Stark, Shauna M; Reagh, Zachariah M; Yassa, Michael A et al. (2018) What's in a context? Cautions, limitations, and potential paths forward. Neurosci Lett 680:77-87
Leal, Stephanie L; Yassa, Michael A (2018) Integrating new findings and examining clinical applications of pattern separation. Nat Neurosci 21:163-173
Weintraub, Sandra; Besser, Lilah; Dodge, Hiroko H et al. (2018) Version 3 of the Alzheimer Disease Centers' Neuropsychological Test Battery in the Uniform Data Set (UDS). Alzheimer Dis Assoc Disord 32:10-17
Kaur, Antarpreet; Edland, Steven D; Peavy, Guerry M (2018) The MoCA-Memory Index Score: An Efficient Alternative to Paragraph Recall for the Detection of Amnestic Mild Cognitive Impairment. Alzheimer Dis Assoc Disord 32:120-124
Wilmoth, Kristin; LoBue, Christian; Clem, Matthew A et al. (2018) Consistency of traumatic brain injury reporting in older adults with and without cognitive impairment. Clin Neuropsychol 32:524-529
Brenowitz, Willa D; Han, Fang; Kukull, Walter A et al. (2018) Treated hypothyroidism is associated with cerebrovascular disease but not Alzheimer's disease pathology in older adults. Neurobiol Aging 62:64-71
Ting, Simon Kang Seng; Foo, Heidi; Chia, Pei Shi et al. (2018) Dyslexic Characteristics of Chinese-Speaking Semantic Variant of Primary Progressive Aphasia. J Neuropsychiatry Clin Neurosci 30:31-37
Gallagher, Damien; Kiss, Alex; Lanctot, Krista L et al. (2018) Toward Prevention of Mild Cognitive Impairment in Older Adults With Depression: An Observational Study of Potentially Modifiable Risk Factors. J Clin Psychiatry 80:

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