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F4‐07‐01: LC AND FRONTOPARIETAL NETWORK FUNCTION IN NORMAL AGING
Author(s) -
Mather Mara,
Clewett David,
Kennedy Briana,
Nielson Shawn,
Huang Ringo,
Velasco Ricardo,
Tu Kristie,
Han Jiyoon
Publication year - 2018
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1016/j.jalz.2018.06.2888
Subject(s) - locus coeruleus , psychology , isometric exercise , cognition , neuroscience , audiology , brain activity and meditation , intraparietal sulcus , medicine , functional magnetic resonance imaging , electroencephalography , central nervous system
disease symptoms. A critical aspect of these abnormalities is immune dysregulation. Neuropathological examination of AD and AD model tissue is essential in gaining a better understanding of the pathogenesis of AD and developing effective therapeutic interventions. Methods: To better understand the heterogeneity of AD pathogenesis we have developed a method that allows localized proteomics on individual cell populations isolated from formalin fixed paraffin embedded tissue sections using laser capture microdissection and LC-MS/MS. We have applied this powerful new technique to compare rapidly progressive AD (rpAD) versus sporadic slowly progressive AD (spAD). We performed the most comprehensive analysis of amyloid plaque associated proteins to date, identifying numerous novel amyloid associated proteins. Importantly, we have shown for the first time that not all amyloid plaques contain the same proteins, suggesting that there may be different subtypes of plaques, which in turn could help to clarify the heterogeneity in AD pathogenesis and better target therapeutic approaches. Given the diversity of the pathogenesis of AD we have developed a number of non-mutually exclusive therapeutic approaches including blocking the interaction between Ab and apolipoprotein E, using peptoids; use of active and passive immunization that is directed against the shared pathological conformation of Ab and tau oligomers concurrently, as well as the stimulation of innate immunity with TLR9 agonist CpG oligodeoxynucleotides. Results: Our results show that these diverse, non-mutually exclusive approaches are efficacious in several different transgenic AD models as well as in a non-human primate model of AD, squirrel monkeys. Conclusions:Our localized proteomic strategy provides new insights into the heterogeneous underpinnings of AD neuropathology, allowing for the development of a number of non-mutually exclusive therapeutic approaches that address immune dysregulation in AD.