Premium
P2‐178: REDUCED NEUROINFLAMMATION AND IMPROVED MEMORY IN OLD MALE C57BL/6J MICE OVEREXPRESSING ADROPIN
Author(s) -
Farr Susan A.,
Goshal Sarbani,
Girardet Clemence,
Niehoff Michael L.,
Mynatt Randall L.,
Kolar Grant R.,
Candelario-Jalil Eduardo,
Butler Andrew A.
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.2018.06.865
Subject(s) - neuroinflammation , hippocampal formation , hippocampus , biology , proinflammatory cytokine , neuroscience , central nervous system , open field , offspring , cognitive decline , inflammation , endocrinology , medicine , dementia , immunology , pregnancy , genetics , disease
Background:Alzheimer’s disease (AD) is the most common form of dementia and is characterised by the accumulation of amyloid-b (Ab) and tau protein in the brain tissue of affected individuals. However, the initial molecular events that lead to the development of AD are still unknown. The deposition of Ab has led to the hypothesis that the disease is initiated by Ab accumulation while genome-wide association studies suggest that inflammation might be critically important in disease pathogenesis. However, the relationship between these key events – the production of Ab in the brain and neuroinflammation is still not well understood.Methods: We investigated the relationship between neuroinflammation and protein aggregation using highly sensitive single-molecule techniques and human neurons derived from induced pluripotent stem cells carrying mutations in APP and PS1 causal for AD. Human neurons were incubated with the proinflammatory cytokine TNFa while the arising proteotoxic environment was monitored using various techniques, including aggregate-specific super-resolution imaging and an assay quantifying the ability of the aggregates to permeabilise lipid membranes. Results:Here we show that physiological levels of TNFa can drive oligomer production over time from neurons derived from human stem cells. Neurons with APP mutations produce significantly higher levels of oligomers than isogenic controls. The oligomers formed in neuronal cells of AD also show a greater propensity to permeabilise lipid membranes, suggesting mechanisms for the observed proteotoxicity in AD. Conclusions:Our work suggests that neuroinflammation and protein aggregation are closely linked and may occur together in a positivefeedback loop during AD. Therapeutic strategies to break this cycle may need to target both neuroinflammation and protein aggregation together.