Biology subjects

Madamanchi, K.

Publications and source records attributed to Madamanchi, K..

2 recordsLinked to original sources

bioRxiv2026

Microbiome Integrity Protects Against Glial-Mediated Tau and Amyloid Pathology Through Circadian and Autophagy Homeostasis

Alzheimers disease (AD) is characterized not only by tau and amyloid-{beta} aggregation but also by systemic disruptions in circadian rhythms, metabolism, and gut-brain communication that exacerbate neuroinflammation and neurodegeneration. While glial cells play central roles in inflammatory signaling and proteostasis, the contribution of the gut microbiome to glia-driven AD pathology remains poorly understood. Here, we used Drosophila models with glial-specific expressions of human tau and amyloid-associated transgenes to investigate how microbiome integrity influences disease progression. AD models exhibited significant shifts in gut microbial composition, particularly in Lactobacillus and Acetobacter species, suggesting an adaptive microbial response to pathological stress. Strikingly, microbiome depletion (axenic condition) markedly worsened behavioral and physiological outcomes, including disrupted sleep-circadian rhythms, impaired memory, and reduced locomotor function. These deficits were accompanied by amplified neuroinflammatory signaling (Upd-Dome-Hop-Stat92e axis), increased apoptotic gene expression, lipid dysregulation, and altered synaptic markers. Moreover, microbiome loss induced energy stress marked by elevated phospho-AMPK (p-AMPK), yet failed to restore proteostasis, as evidenced by accumulation of ubiquitinated proteins and the autophagy adaptor Ref2p, indicating impaired autophagic flux. This dysfunction correlated with increased tau, phospho-tau, and A{beta}42 accumulation. Together, our findings demonstrate that microbiome depletion exacerbates glial-mediated inflammation, disrupts circadian and metabolic homeostasis, impairs, and accelerates cognitive and motor decline. This work highlights a previously underappreciated role of the gut microbiome in restraining glial dysfunction and mitigating AD-like pathology, positioning microbial homeostasis as a critical modulator of neurodegenerative disease progression.

neuroscience↗

bioRxiv2025

Regulation of lipid dysmetabolism and neuroinflammation linked with Alzheimer's disease through modulation of Dgat2

Alzheimers disease (AD), an age-associated neurodegenerative disorder, is characterized by progressive cognitive decline, amyloid-{beta} (A{beta}) deposition, lipid dysregulation, and neuroinflammation. Although mutations in the amyloid precursor protein (APP) and accumulation of A{beta}42 are established drivers of pathology, the mechanisms connecting amyloid toxicity with lipid metabolism and inflammatory responses remain poorly understood. Here, we employed complementary Drosophila and mouse models to dissect these relationships. Expression of AppNLG and A{beta}42 in Drosophila resulted in locomotor deficits, disrupted sleep-circadian rhythms, memory impairments, lipid accumulation, synaptic loss, and neuroinflammatory signatures. Comparable lipid metabolic disturbances and inflammatory alterations were detected in the AppNLG-F knock-in mouse model, underscoring their conserved relevance to AD pathogenesis. We further identified diacylglycerol O-acyltransferase 2 (Dgat2), a key enzyme catalyzing the final step of triglyceride synthesis, as a critical modulator of AD-related phenotypes. Dgat2 expression was altered in both animal models and human AD tissues. Notably, panneuronal knockdown of Dgat2 in Drosophila attenuated lipid accumulation, restored synaptic integrity, and ameliorated locomotor and cognitive deficits, while also reducing neuroinflammation. Dgat2 suppression additionally improved sleep and circadian behavior, highlighting its pleiotropic protective effects. Together, these findings demonstrate a mechanistic link between amyloid pathology, lipid dysregulation, and neuroinflammatory processes. Targeting Dgat2 may therefore represent a novel therapeutic strategy to counteract AD-associated metabolic and neuronal dysfunction. The conservation of lipid homeostasis mechanisms across species underscores the translational potential of this approach for delaying or mitigating AD progression.

physiology↗