Hydroxychloroquine Lowers the Risk of Alzheimer's Disease and Rescues Its Molecular Phenotypes - medtigo



Hydroxychloroquine Lowers the Risk of Alzheimer’s Disease and Rescues Its Molecular Phenotypes

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According to a study published in Nature, researchers have proposed the Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway as a possible therapeutic target for Alzheimer’s disease (AD).

They postulate that hydroxychloroquine (HCQ) may impact the genesis and risk of Alzheimer’s disease since recent research shows that HCQ can suppress STAT3. Compared to methotrexate, the introduction of HCQ was linked with a reduced incidence of incident AD in 109,124 individuals with rheumatoid arthritis under regular clinical treatment.

They further show that HCQ improves hippocampal synaptic plasticity in APP/PS1 animals, avoiding amyloid plaque development and neurodegeneration. HCQ has a dose-dependent influence on LTP.  

Furthermore, in cell culture-based phenotypic tests, HCQ administration enhances microglial clearance of A1-42 while decreasing neuroinflammation and tau phosphorylation. Researchers also conclude that HCQ’s impacts on Alzheimer’s disease pathogenesis are most likely mediated by STAT3 suppression in microglia, neurons, and astrocytes.

A medication called hydroxycitric acid (HCQ) is currently available to treat Alzheimer’s disease, and it has demonstrated encouraging benefits in animal models (AD). Large-scale clinical research, including people at risk throughout the preclinical phases of disease development, is necessary to test this idea adequately.  

Despite tremendous advances in understanding the biology behind Alzheimer’s disease (AD), the discovery of viable therapeutics has lagged. Traditional drug development strategies have concentrated on amyloid plaques and neurofibrillary tangles, two hallmarks of Alzheimer’s disease. However, these diseases may result from a chain reaction that begins decades before they manifest.

Finding early genetic anomalies in disease development may thus be critical to designing successful Alzheimer’s therapies. Furthermore, there is mounting evidence that drugs that impact many major pathogenic pathways simultaneously may be more successful than those that only affect one.

Some findings imply that HCQ is more effective than MTX in avoiding incident ADRD and restoring AD-related deficits, such as decreased hippocampal synaptic plasticity and dysfunction in the three major AD pathogenesis pathways of neuroinflammation, A clearance, and tau phosphorylation. The inactivation of the cytokine transducer protein STAT3 might explain these findings.


Despite previous research in transgenic AD animal models indicating enhanced STAT3 signaling in A-induced neuronal death, reactive astrogliosis, inadequate microglial clearance of A, and cognitive impairment [49, 50], recent data shows that HCQ inactivates STAT3 [11]. Inhibiting STAT3 signaling may be a promising therapeutic method for Alzheimer’s disease since it addresses numerous molecular issues.  

 To see if STAT3 inactivation is associated with HCQ’s disease-modifying effects, they first discovered that HCQ inactivates STAT3 in astrocytes, microglia, and primary cortical neurons from mice. They also discovered that inactivating STAT3 in APP/PS1 hippocampi with HCQ dramatically decreases p-STAT3 levels, indicating that this is related to the repair of defective hippocampal synaptic plasticity.

These preliminary mechanistic experiments imply that STAT3 inactivation may be the mechanism via which HCQ impacts ADRD. Finally, they showed that HCQ, a commonly used RA treatment, lowers the risk of AD in the elderly by addressing numerous risk variables implicated in the disease’s progression: synaptic dysfunction, neuroinflammation, amyloid- (A) clearance, and tau phosphorylation.

According to some of the findings, this medicine, which is both cheap and free of substantial side effects, can be used as a disease-modifying therapy for Alzheimer’s disease. To confirm the findings in at-risk patients throughout the preclinical phases of disease development, it is critical to launching clinical trials with large enough sample numbers to draw accurate conclusions as soon as possible. 

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