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P3‐070: ANALYSIS OF A SPORADIC MOUSE MODEL OF ALZHEIMER'S DISEASE
Author(s) -
Vitek Michael P.,
Badea Alexandra,
Lutz Michael W.,
Mukherjee Sayan,
Thompson J. Will,
Sundseth Stuart,
Colton Carol 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.2018.06.1426
Subject(s) - neurodegeneration , knockout mouse , disease , neuroscience , biology , immune system , pathological , gene , medicine , pathology , immunology , genetics
Background: Alzheimer’s disease (AD) shares risk factors with cardiovascular disease (CVD); altered cholesterol metabolism may be a common mechanism. Cholesterol efflux capacity (CEC), an ex vivo metric of plasma high-density lipoprotein (HDL) function, predicts incident CVD inversely and independently of other risk factors. Central nervous system (CNS) cholesterol excess may promote neurodegeneration; CEC of cerebrospinal fluid (CSF) may be a useful index of CNS cholesterol trafficking, with higher CSF CEC being neuroprotective. We hypothesized reduced CSF CEC in AD vs. cognitively normal (CN) subjects, and compared plasma vs. CSF CEC in AD, MCI, and CN subjects. Methods: We retrieved CSF and same-day EDTA plasma from 104 Caucasian subjects (37 AD (17M); 18 MCI (14M); and 49 CN (24M)) from the Center for Neurodegenerative Diseases biobank at the Perelman School of Medicine. The CSF CEC assay used N9 mouse microglial cells labeled with [H]-cholesterol for 24h, ABCA1 expression upregulated with 0.3 mM cyclic AMP for 6h, exposed to 33 ml of CSF, then incubated for 2.5h. We used a similar assay with J774 mouse macrophages for plasma CEC. CEC was quantified as percent [H]cholesterol counts in the medium of total counts medium+cells, normalized to a pool sample. Results: CSF CEC was significantly (22%) lower in female vs. male CN subjects (1.026(S.D.)0.21% vs. 1.3160.29%, P1⁄40.0005); subsequent analyses were stratified by sex. CSF CECwas not correlated with age. CSF CECwas significantly (P<0.05) lower in males with AD orMCI vs. CN (AD+MCI vs. CN, P1⁄40.008). CSF CEC did not differ significantly between female MCI or AD subjects vs. CN. Plasma CEC was significantly higher in females than males (1.2460.24% vs. 1.0060.20%, P<0.001), but did not differ by diagnosis. Plasma and CSF CEC were not correlated. Conclusions: CSF CEC was lower in female vs. male CN subjects, and was lower in males with AD or MCI vs. CN. Plasma and CSF CEC were unrelated. The reduced CSF CEC in male MCI vs. CN subjects suggests that this feature may be present in early or mild AD. Further studies are needed to confirm these findings and to delineate the pathophysiologic role of CSF CEC in AD.