Synaptoprotective effects of the novel TNF inhibitor XPRO1595 in 5xFAD mice: Interactions between Western diet and sex: Molecular and cell biology/neuroinflammation. (7th December 2020)

• Record Type: Journal Article
• Authors: Weiss, Blaine E.; Gollihue, Jenna L.; Farr, N. Drew; Sompol, Pradoldej; Artiushin, Irina A.; Kraner, Susan D.; Tansey, Malu Gamez; Norris, Christopher M.
• Is Part Of: Alzheimer's & dementia. Volume 16(2020)Supplement 2
• Page Start: n/a
• Page End: n/a
• Publication Date: 2020-12-07
• Subjects: Alzheimer's disease -- Periodicals; Alzheimer Disease -- Periodicals; Dementia -- Periodicals; Démence; Maladie d'Alzheimer; Périodique électronique (Descripteur de forme); Ressource Internet (Descripteur de forme); 616.83
• DOI: 10.1002/alz.043621
• Languages: English
• ISSNs: 1552-5260

Abstract

Abstract: Background: The western diet has been repeatedly shown to trigger inflammation and has been implicated as an environmental factor in cerebrovascular disease and Alzheimer's disease (AD) pathology. Our previous work has shown that inhibition of neuroinflammation by the selective anti‐TNF biologic, XPro1595, ameliorates neurologic dysfunction in a mouse model of amyloid pathology. Unlike other TNF inhibitors, XPro1595 targets only the soluble form of TNF (sTNF), preserving the neuroprotective transmembrane TNF signaling pathways. Here, we investigate whether western diet‐induced chronic inflammation accelerates AD‐like pathology in a mouse with genetic predisposition for amyloid development and the extent to which this synergy is dependent on sTNF signaling. Method: Three‐month‐old 5xFAD mice received Teklad high fat and high fructose (HFHF) diet (TD 150111) or a balanced control diet (TD 150112) over a two‐month period. At four‐months‐of‐age and halfway through dietary intervention, subcutaneous injections of XPro1595 (10mg/kg, 2x/week) or saline were started and continued for another 4 weeks along with the dietary regimen. At endpoint, brain slices were prepared for electrophysiologic analyses of basal synaptic function and long‐term potentiation (LTP) in hippocampal CA1. Synaptic parameters were compared across diet and drug treatment conditions (n= 9‐14 mice/condition) using ANOVA and, where appropriate, Tukey's post hoc test. Result: Slices from XPro1595‐treated mice exhibited an increase in both synaptic strength and LTP, regardless of diet. However, these effects also depended strongly on sex. LTP in males was similar across treatment groups (125‐130% of baseline), but females treated with HFHF showed nearly no LTP. LTP deficits in HFHF‐treated females were reversed by XPro1595 adminitration in vivo . In fact, HFHF females treated with XPro1595 showed the highest LTP levels (∼140% of baseline) of all groups investigated. Conclusion: Aberration of sTNF pathways have a differential effect on synapse physiology depending on sex and diet. Protective effects of XPro1595 on synapes materialize predominantly in females under conditions of dietary stress, while males responded modestly to treatment regardless of diet conditions. Studies are underway to establish whether sex‐specific differences reflect differences in amyloid burden between the sexes known to occur in this model, or are related to other differences unrelated to amyloid burden.