TY - JOUR
T1 - Hydroxychloroquine lowers Alzheimer’s disease and related dementias risk and rescues molecular phenotypes related to Alzheimer’s disease
AU - Varma, Vijay R.
AU - Desai, Rishi J.
AU - Navakkode, Sheeja
AU - Wong, Lik Wei
AU - Anerillas, Carlos
AU - Loeffler, Tina
AU - Schilcher, Irene
AU - Mahesri, Mufaddal
AU - Chin, Kristyn
AU - Horton, Daniel B.
AU - Kim, Seoyoung C.
AU - Gerhard, Tobias
AU - Segal, Jodi B.
AU - Schneeweiss, Sebastian
AU - Gorospe, Myriam
AU - Sajikumar, Sreedharan
AU - Thambisetty, Madhav
N1 - Funding Information:
This research was supported in part by the intramural program of the National Institute on Aging (NIA). MT is grateful for funding support from the Andrew and Lillian A. Posey foundation to the Clinical and Translational Neuroscience Section, Laboratory of Behavioral Neuroscience, NIA. SN, LWW and SS are supported by Singapore Ministry of Education Academic Research Fund Tier 3 (MOE2017-T3-1-002) and NUSMED-FOS Joint Research Programme grant (NUHSRO/2018/075/NUSMed-FoS/01).
Publisher Copyright:
© 2022, This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.
PY - 2023/3
Y1 - 2023/3
N2 - We recently nominated cytokine signaling through the Janus-kinase–signal transducer and activator of transcription (JAK/STAT) pathway as a potential AD drug target. As hydroxychloroquine (HCQ) has recently been shown to inactivate STAT3, we hypothesized that it may impact AD pathogenesis and risk. Among 109,124 rheumatoid arthritis patients from routine clinical care, HCQ initiation was associated with a lower risk of incident AD compared to methotrexate initiation across 4 alternative analyses schemes addressing specific types of biases including informative censoring, reverse causality, and outcome misclassification (hazard ratio [95% confidence interval] of 0.92 [0.83–1.00], 0.87 [0.81–0.93], 0.84 [0.76–0.93], and 0.87 [0.75–1.01]). We additionally show that HCQ exerts dose-dependent effects on late long-term potentiation (LTP) and rescues impaired hippocampal synaptic plasticity prior to significant accumulation of amyloid plaques and neurodegeneration in APP/PS1 mice. Additionally, HCQ treatment enhances microglial clearance of Aβ1-42, lowers neuroinflammation, and reduces tau phosphorylation in cell culture-based phenotypic assays. Finally, we show that HCQ inactivates STAT3 in microglia, neurons, and astrocytes suggesting a plausible mechanism associated with its observed effects on AD pathogenesis. HCQ, a relatively safe and inexpensive drug in current use may be a promising disease-modifying AD treatment. This hypothesis merits testing through adequately powered clinical trials in at-risk individuals during preclinical stages of disease progression.
AB - We recently nominated cytokine signaling through the Janus-kinase–signal transducer and activator of transcription (JAK/STAT) pathway as a potential AD drug target. As hydroxychloroquine (HCQ) has recently been shown to inactivate STAT3, we hypothesized that it may impact AD pathogenesis and risk. Among 109,124 rheumatoid arthritis patients from routine clinical care, HCQ initiation was associated with a lower risk of incident AD compared to methotrexate initiation across 4 alternative analyses schemes addressing specific types of biases including informative censoring, reverse causality, and outcome misclassification (hazard ratio [95% confidence interval] of 0.92 [0.83–1.00], 0.87 [0.81–0.93], 0.84 [0.76–0.93], and 0.87 [0.75–1.01]). We additionally show that HCQ exerts dose-dependent effects on late long-term potentiation (LTP) and rescues impaired hippocampal synaptic plasticity prior to significant accumulation of amyloid plaques and neurodegeneration in APP/PS1 mice. Additionally, HCQ treatment enhances microglial clearance of Aβ1-42, lowers neuroinflammation, and reduces tau phosphorylation in cell culture-based phenotypic assays. Finally, we show that HCQ inactivates STAT3 in microglia, neurons, and astrocytes suggesting a plausible mechanism associated with its observed effects on AD pathogenesis. HCQ, a relatively safe and inexpensive drug in current use may be a promising disease-modifying AD treatment. This hypothesis merits testing through adequately powered clinical trials in at-risk individuals during preclinical stages of disease progression.
UR - http://www.scopus.com/inward/record.url?scp=85145067749&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85145067749&partnerID=8YFLogxK
U2 - 10.1038/s41380-022-01912-0
DO - 10.1038/s41380-022-01912-0
M3 - Article
C2 - 36577843
AN - SCOPUS:85145067749
SN - 1359-4184
VL - 28
SP - 1312
EP - 1326
JO - Molecular psychiatry
JF - Molecular psychiatry
IS - 3
ER -