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Repurposing Trazodone for Alzheimer's Disease to Modulate Soluble ST2 Levels and Alleviate Alzheimer's Pathology

ABSTRACT: Drug repurposing offers a cost-effective strategy for accelerating therapeutic development. This study identifies trazodone, an FDA-approved anti-depressant, as a promising therapeutic candidate for Alzheimer’s disease (AD). We show that trazodone use in patients with AD is associated with decreased levels of soluble ST2 (sST2), a known disease-modifying factor in AD. In the APP/PS1 transgenic mouse model of AD, trazodone treatment enhances microglial interactions with amyloid-beta (Aβ) and alleviates Aβ pathology. Additionally, trazodone rescues synaptic deficits and restores the expression of synaptic proteins in APP/PS1 mice. These findings demonstrate the therapeutic potential of repurposing trazodone to target immune and synaptic dysfunctions in AD, providing a novel therapeutic avenue for this debilitating condition.

INSTRUMENT(S):

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Brain, Synapse

DISEASE(S): Alzheimer's Disease

SUBMITTER: Daniel Yew Kit Wong

LAB HEAD: Nancy Yuk-Yu

PROVIDER: PXD071776 | Pride | 2026-07-02

REPOSITORIES: Pride

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Dataset's files

Source:

			Action	DRS
	20250630_161439_250630_Daniel_D.sne	Other
	DAC1_S2-C11_1_11240.d.zip	Other
	DAC2_S2-D11_1_11243.d.zip	Other
	DAC3_S2-E11_1_11244.d.zip	Other
	DAC4_S2-F11_1_11241.d.zip	Other

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Project description:Backgroud Alzheimer's disease (AD) is a progressive and irreversible neurodegenerative disorder for which there is currently no cure, representing a serious clinical challenge. Lysine 2-hydroxyisobutyrylation (Khib) is a newly discovered post-translational modification that has been found to be widespread in a variety of organisms in recent years and is involved in important biometabolic processes that regulate protein function. However, it is unclear whether and how protein Khib modifications are involved in AD. This study aimed to explore the involvement of Khib in AD and its underlying mechanisms. Methods We compared a series of lysine acylation modification patterns between 9-month-old APP/PS1 mice and wild-type (WT) control mice by Western blot assays. Quantitative Khib proteomic analysis identified Khib modification proteins and key sites associated with AD. Using stereotactic brain injection, we delivered adeno- associated viruse (AAV) overexpressing Clusterin (CLU) K436R (lysine to arginine mutation at site 436, mimicking Khib deficiency) into the bilateral lateral ventricles of 9-month-old WT and APP/PS1 mice. Additionally, C8-D1A cells were infected with lentivirus carrying CLU K436 mutation. These approaches enabled functional assessment of CLU K436 khib modification in AD pathogenesis. Furthermore, co-immunoprecipitation analyses revealed that CLU K436 khib modification modulates the interaction between CLU and Aβ. Results The level of Khib was significantly increased in 9-month-old APP/PS1 mice. Quantitative Khib analysis identified Clusterin (CLU) as a differentially modified protein, with K436 serving as its primary Khib modification site. Further investigation revealed that CLU K436 Khib levels was upregulated in APP/PS1 AD model mice. Loss of K436 Khib in CLU K436R mutant APP/PS1 mice notably ameliorated β-amyloid plaque, gliosis, and neuroinflammation, consequently mitigating memory deficits in vivo. The lentiviral vector carrying CLU K436R mutant in C8-D1A astrocyte cell enhanced glial cell activation and cell survival in vitro. Mechanistically, CLU K436 Khib modification may affect Aβ metabolism by impacting the interaction between CLU and Aβ. Conclusions Our results indicated the role of Khib in AD, elucidating the function and potential molecular mechanism of CLU K436 Khib modification in AD. These findings offer novel perspectives on therapeutic approaches for AD.

Project description:1,7-bis(4-hydroxy-3-methoxyphenyl)heptane-3,5-dione (tetrahydrocurcumin, THC) is a major bioactive metabolite of curcumin (the principal active ingredient of Curcuma longa L.), and overcomes the low bioavailability of curcumin, demonstrating the potential anti-inflammatory, antioxidant and neuroprotective properties, etc, some of which were considered to be even superior to curcumin. In the present study, the protective properties of THC in the hippocampus of APP/PS1 mice, and the effects of THC against Aβ-induced toxicity in BV-2 cells were explored. The data in vitro showed that Aβ induced decreased cell viability, and cell cycle arrest and apoptosis in BV-2 cells, which could be ameliorated by THC. In vivo, THC administration was able to rescue learning and memory, and reduce Aβ burden in the hippocampus of APP/PS1 mice. By comprehensive proteomic analysis of the hippocampus of mice, a total of 157 differentially expressed proteins were identified in APP/PS1 mice treated with THC (comparing with APP/PS1 mice), which were enriched in “T cell activation”, “lymphocyte proliferation” and “protein oligomerization”, etc. The results of Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis suggested that the effects of THC on the cell cycle and apoptosis were mostly related to the “Ras signaling pathway” and “JAK−STAT signaling pathway”, etc. Using Western blot and ELISA, the down-regulation of Gab2 and K-Ras, and the up-regulation of caspase-3, TGF-β1 and TNF-ɑ were found in APP/PS1 mice. THC attenuated the abnormal expression of Gab2, K-Ras, caspase-3 and TNF-ɑ, and up-regulated Bag1 and TGF-β1 expression in APP/PS1 mice. In BV-2 cells, Aβ induced the down-regulation of Gab2, K-Ras and TGF-β1, and the overexpression of caspase-3, PARP1, cleaved-PARP1 and TNF-ɑ, which were markedly restored by THC. Moreover, THC up-regulated Bag1 expression in BV-2 cells treated with Aβ. The decreased transcriptional expression levels of Ccnd2 and Cdkn1a was also observed in Aβ-treated BV-2 cells. THC treatment alleviated down-regulation of Ccnd2, but did not affect the abnormal transcriptional expression of Cdkn1a caused by Aβ in BV-2 cells. For the first time, we identified that the action of THC in preventing AD was associated with inhibition of cell cycle arrest and apoptosis of microglia via the Ras/ERK signaling pathway, shedding new light on the role of THC in alleviating the progression of AD.

Project description:Background Microglial cell iron load and inflammatory activation are significant hallmarks of late-stage Alzheimer’s disease (AD). In vitro, microglia preferentially upregulate iron importer, divalent metal transporter 1 (DMT1, gene name Slc11a2) in response to inflammatory stimuli, and excess iron can augment cellular inflammation, suggesting a feed-forward loop between iron import mechanisms and inflammatory signaling. However, it is not understood whether microglial iron import mechanisms directly contribute to inflammatory signaling and chronic disease in vivo. These studies determined the effects of knocking down microglial iron import gene, Slc11a2, on AD-related cognitive decline and microglial transcriptional phenotype. Methods In vitro experiments and RT-qPCR were used to assess a role for DMT1 in amyloid-β-associated inflammation. To determine the effects of microglial Slc11a2 knockdown on AD-related phenotypes in vivo, triple-transgenic Cx3cr1Cre-ERT2;Slc11a2flfl;APP/PS1+ or – mice were generated and administered corn oil or tamoxifen to induce knockdown at 5-6 months of age. Both sexes underwent behavioral analyses to assess cognition and memory (12-15 months of age). Hippocampal CD11b+ microglia were magnetically isolated from female mice (15-17 months) and bulk RNA-sequencing analysis was conducted. Results DMT1 inhibition in vitro robustly decreased Aβ-induced inflammatory gene expression and cellular iron levels in conditions of excess iron. In vivo, Slc11a2KD APP/PS1 female, but not male, mice displayed a significant worsening of memory function in Morris water maze and a fear conditioning assay, along with significant hyperactivity compared to control WT and APP/PS1 mice. Hippocampal microglia from Slc11a2KD APP/PS1 females displayed significant increases in genes Enpp2, Ttr, and iron-export gene, Slc40a1, compared to control APP/PS1 cells. Slc11a2KD cells from APP/PS1 females also exhibited decreased expression of markers related to disease-associated microglia (DAMs), such as Apoe, Ctsb, Csf1, and Hif1α. Conclusions This work suggests a sex-specific role for microglial iron import gene Slc11a2 in propagating behavioral and cognitive phenotypes in the APP/PS1 model of AD. These data also highlight an association between loss of a DAM-like phenotype in female microglia and cognitive deficits in Slc11a2KD APP/PS1 mice. Overall, this work illuminates an iron-related pathway in microglia that may serve a protective role during disease and offers insight into mechanisms behind disease-related sex differences.

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Repurposing Trazodone for Alzheimer's Disease to Modulate Soluble ST2 Levels and Alleviate Alzheimer's Pathology

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