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C-KIT inhibitors reduce pathology and improve behavior in the Tg(SwDI) model of Alzheimer's disease.

ABSTRACT: Treatments for Alzheimer's disease have primarily focused on removing brain amyloid plaques to improve cognitive outcomes in patients. We developed small compounds, known as BK40143 and BK40197, and we hypothesize that these drugs alleviate microglial-mediated neuroinflammation and induce autophagic clearance of neurotoxic proteins to improve behavior in models of neurodegeneration. Specificity binding assays of BK40143 and BK40197 showed primary binding to c-KIT/Platelet Derived Growth Factor Receptors (PDGFR)α/β, whereas BK40197 also differentially binds to FYVE finger-containing phosphoinositide kinase (PIKFYVE). Both compounds penetrate the CNS, and treatment with these drugs inhibited the maturation of peripheral mast cells in transgenic mice, correlating with cognitive improvements on measures of memory and anxiety. In the brain, microglial activation was profoundly attenuated and amyloid-beta and tau were reduced via autophagy. Multi-kinase inhibition, including c-KIT, exerts multifunctional effects to reduce neurodegenerative pathology via autophagy and microglial activity and may represent a potential therapeutic option for neurodegeneration.

SUBMITTER: Stevenson M

PROVIDER: S-EPMC11249953 | biostudies-literature | 2024 Oct

REPOSITORIES: biostudies-literature

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c-KIT inhibitors reduce pathology and improve behavior in the Tg(SwDI) model of Alzheimer's disease.

Stevenson Max M Hebron Michaeline L ML Liu Xiaoguang X Balaraman Kaluvu K Wolf Christian C Moussa Charbel C

Life science alliance 20240715 10

Treatments for Alzheimer's disease have primarily focused on removing brain amyloid plaques to improve cognitive outcomes in patients. We developed small compounds, known as BK40143 and BK40197, and we hypothesize that these drugs alleviate microglial-mediated neuroinflammation and induce autophagic clearance of neurotoxic proteins to improve behavior in models of neurodegeneration. Specificity binding assays of BK40143 and BK40197 showed primary binding to c-KIT/Platelet Derived Growth Factor R ...[more]

PMID: 39009412

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Project description:Alzheimer's disease (AD) is characterized by the presence of parenchymal amyloid-? (A?) plaques, cerebral amyloid angiopathy (CAA) and neurofibrillary tangles. Currently there are no effective treatments for AD. Immunotherapeutic approaches under development are hampered by complications related to ineffectual clearance of CAA. Genome-wide association studies have demonstrated the importance of microglia in AD pathogenesis. Microglia are the primary innate immune cells of the brain. Depending on their activation state and environment, microglia can be beneficial or detrimental. In our prior work, we showed that stimulation of innate immunity with Toll-like receptor 9 agonist, class B CpG (cytosine-phosphate-guanine) oligodeoxynucleotides (ODNs), can reduce amyloid and tau pathologies without causing toxicity in Tg2576 and 3xTg-AD mouse models. However, these transgenic mice have relatively little CAA. In the current study, we evaluated the therapeutic profile of CpG ODN in a triple transgenic mouse model, Tg-SwDI, with abundant vascular amyloid, in association with low levels of parenchymal amyloid deposits. Peripheral administration of CpG ODN, both before and after the development of CAA, negated short-term memory deficits, as assessed by object-recognition tests, and was effective at improving spatial and working memory evaluated using a radial arm maze. These findings were associated with significant reductions of CAA pathology lacking adverse effects. Together, our extensive evidence suggests that this innovative immunomodulation may be a safe approach to ameliorate all hallmarks of AD pathology, supporting the potential clinical applicability of CpG ODN. SIGNIFICANCE STATEMENT:Recent genetic studies have underscored the emerging role of microglia in Alzheimer's disease (AD) pathogenesis. Microglia lose their amyloid-?-clearing capabilities with age and as AD progresses. Therefore, the ability to modulate microglia profiles offers a promising therapeutic avenue for reducing AD pathology. Current immunotherapeutic approaches have been limited by poor clearance of a core AD lesion, cerebral amyloid angiopathy (CAA). The present study used Tg-SwDI mice, which have extensive CAA. We found that stimulation of the innate immune system and microglia/macrophage activation via Toll-like receptor 9 using CpG (cytosine-phosphate-guanine) oligodeoxynucleotides (ODNs) leads to cognitive improvements and CAA reduction, without associated toxicity. Our data indicate that this novel concept of immunomodulation represents a safer method to reduce all aspects of AD pathology and provide essential information for potential clinical use of CpG ODN.

Project description:BACKGROUND:Alzheimer's disease (AD) is characterized by physiologically endogenous proteins amyloid beta (A?) and tau undergoing a conformational change and accumulating as soluble oligomers and insoluble aggregates. Tau and A? soluble oligomers, which contain extensive ?-sheet secondary structure, are thought to be the most toxic forms. The objective of this study was to determine the ability of TWF9, an anti-?-sheet conformation antibody (a?ComAb), to selectively recognize pathological A? and phosphorylated tau in AD human tissue compared with cognitively normal age-matched controls and to improve the performance of old 3xTg-AD mice with advanced pathology in behavioral testing after acute treatment with TWF9. METHODS:In this study, we used immunohistochemistry, immunoprecipitation, and enzyme-linked immunosorbent assay (ELISA) to characterize TWF9 specificity. We further assessed cognitive performance in old (18-22 months) 3xTg-AD mice using both a Barnes maze and novel object recognition after intraperitoneal administration of TWF9 (4 mg/kg) biweekly for 2 weeks before the start of behavioral testing. Injections continued for the duration of the behavioral testing, which lasted 2 weeks. RESULTS:Histological analysis of TWF9 in formalin-fixed paraffin-embedded human control and AD (ABC score: A3B3C3) brain tissue revealed preferential cytoplasmic immunoreactivity in neurons in the AD tissue compared with controls (p?<?0.05). Furthermore, ELISA using oligomeric and monomeric A? showed a preferential affinity for oligomeric A?. Immunoprecipitation studies showed that TWF9 extracted both phosphorylated tau (p?<?0.01) and A? (p?<?0.01) from fresh frozen brain tissues. Results show that treated old 3xTg-AD mice have an enhanced novel object recognition memory (p?<?0.01) and Barnes maze performance (p?=?0.05) compared with control animals. Overall plaque burden, neurofibrillary tangles, microgliosis, and astrocytosis remained unchanged. Soluble phosphorylated tau was significantly reduced in TWF9-treated mice (p?<?0.05), and there was a trend for a reduction in soluble A? levels in the brain homogenates of female 3xTg-AD mice (p?=?0.06). CONCLUSIONS:This study shows that acute treatment with an a?ComAb can effectively improve performance in behavioral testing without reduction of amyloid plaque burden, and that peripherally administered IgG can affect levels of pathological species in the brain.

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C-KIT inhibitors reduce pathology and improve behavior in the Tg(SwDI) model of Alzheimer's disease.

Publications

c-KIT inhibitors reduce pathology and improve behavior in the Tg(SwDI) model of Alzheimer's disease.

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