Activation of CREB‐mediated autophagy by thioperamide ameliorates β‐amyloid pathology and cognition in Alzheimer’s disease

Abstract

Alzheimer's disease (AD) is an age‐related neurodegenerative disease, and the imbalance between production and clearance of β‐amyloid (Aβ) is involved in its pathogenesis. Autophagy is an intracellular degradation pathway whereby leads to removal of aggregated proteins, up‐regulation of which may be a plausible therapeutic strategy for the treatment of AD. Histamine H3 receptor (H3R) is a presynaptic autoreceptor regulating histamine release via negative feedback way. Our previous study showed that thioperamide, as an antagonist of H3R, enhances autophagy and protects against ischemic injury. However, the effect of thioperamide on autophagic function and Aβ pathology in AD remains unknown. In this study, we found that thioperamide promoted cognitive function, ameliorated neuronal loss, and Aβ pathology in APP/PS1 transgenic (Tg) mice. Interestingly, thioperamide up‐regulated autophagic level and lysosomal function both in APP/PS1 Tg mice and in primary neurons under Aβ‐induced injury. The neuroprotection by thioperamide against AD was reversed by 3‐MA, inhibitor of autophagy, and siRNA of Atg7, key autophagic‐related gene. Furthermore, inhibition of activity of CREB, H3R downstream signaling, by H89 reversed the effect of thioperamide on promoted cell viability, activated autophagic flux, and increased autophagic‐lysosomal proteins expression, including Atg7, TFEB, and LAMP1, suggesting a CREB‐dependent autophagic activation by thioperamide in AD. Taken together, these results suggested that H3R antagonist thioperamide improved cognitive impairment in APP/PS1 Tg mice via modulation of the CREB‐mediated autophagy and lysosomal pathway, which contributed to Aβ clearance. This study uncovered a novel mechanism involving autophagic regulating behind the therapeutic effect of thioperamide in AD.

The pleiotropic roles of autophagy in Alzheimer's disease: From pathophysiology to therapy

“…Because of their wide expression in the brain and their role in modulating autophagy by sensing extracellular metabolites, G-protein–coupled receptors emerge as druggable targets in neurodegeneration. Chemical inhibition of H3R (thioperamide) and 5-HT2AR (desloratadine) promotes autophagy by CREB-mediated upregulation of TFEB/ATG7/LAMP1 (in neurons) and SIRT1 (in microglia), respectively, and significantly reduces Aβ levels in the APP/PS1 mouse model [ 49 , 50 ]. Interestingly, allosteric inhibition of mGluR5 by CTEP restarted autophagy and rescued Aβ pathology in male APPswe/PS1ΔE9 mice, but not in their female counterparts.…”

Pharmacological modulation of autophagy for Alzheimer's disease therapy: Opportunities and obstacles

“… 199 Selenomethionine Induction mTOR inhibition A β -incubated PC12 A β injected-mouse Increase cell viability Prevent cognitive deficits 100 μmol/L 6 μg/mL in drinking water 200 Dihydroartemisinin Induction mTOR inhibition SwAPP-N2a SwAPP-SH-SY5Y APPSwe/PSEN1dE9 transgenic mouse Reduce A β and APP levels Improve memory impairment 1 μmol/L 20 mg/kg (Oral administration) 201 Thioperamide Induction CREB-1-mediated autophagy A β -incubated mouse primary cortical neurons APPSwe/PSEN1dE9 transgenic mouse Reduce A β level Ameliorate neuronal loss Prevent cognitive deficits 1 μmol/L 1–5 mg/kg (i.p.) 202 …”

Inhibition of Astrocytic Histamine N-Methyltransferase as a Possible Target for the Treatment of Alzheimer’s Disease

“…Wang et al found that thioperamide administration improves cognitive function, lowers neuronal damage, and reduces Aβ pathology in APP/PS1 transgenic (Tg) mice. According to their results, the beneficial effect has been achieved by increasing Aβ clearance by favoring autophagy and lysosomal processing [160].…”