Fig. 1: Study design and key findings.
A We first demonstrated that in a large, real-world clinical dataset using Medicare claims data, exposure to HCQ reduces risk of incident ADRD in RA patients relative to the active comparator, methotrexate (MTX). B We next showed that HCQ rescues impaired hippocampal synaptic plasticity assessed by late long-term potentiation (LTP) in the APP/PS1 transgenic mouse model of AD. C We demonstrated that HCQ rescues molecular abnormalities associated with AD including reduction in LPS-induced neuroinflammation, increase in Aβ1-42 phagocytosis by microglia; and lowering of tau phosphorylation. D We finally demonstrated that HCQ inactivates STAT3 in microglia, astrocytes, and neurons. HCQ hydroxychloroquine, AD Alzheimer’s disease, LPS bacterial lipopolysaccharide, IL-1β interleukin 1 beta, TNF-α tumor necrosis factor alpha, Aβ1-42 amyloid-beta 1-42, APP/PS1 double transgenic mice expressing mutant human amyloid precursor protein and mutant human presenilin 1, SC Schaffer collateral pathway, CA1 cornu ammonis 1, CA3 cornu ammonis 3, MF mossy fiber, Rec recording electrode, S1 apical dendritic input, S2 basal dendritic input, MPP medial perforant path, fEPSP field excitatory postsynaptic potentials, STET strong tetanization, ADRD Alzheimer’s disease and related dementias, MTX methotrexate, RA rheumatoid arthritis.
