Biology subjects

Iyer, A. K.

Publications and source records attributed to Iyer, A. K..

4 recordsLinked to original sources

bioRxiv2026

MAPT regulates autophagic-lysosomal function and phagocytosis in human microglia

Tauopathies are characterized by the accumulation and spread of pathogenic tau aggregates throughout the brain, a process that is increasingly recognized to involve not only neurons but also microglia. However, whether pathogenic MAPT directly alters microglial degradative capacity remains poorly understood. Here, using isogenic human induced pluripotent stem cell-derived microglia carrying the pathogenic MAPT IVS10+16 mutation, we identify tau as a regulator of microglial lysosomal function. MAPT IVS10+16 microglia exhibited coordinated suppression of lysosomal and autophagic pathways, reduced lysosomal protease abundance and activity, and impaired autophagosome-lysosome fusion. Mutant microglia also showed reduced uptake of extracellular tau aggregates, reduced tau accumulation in acidic compartments, and a blunted lysosomal response to proteopathic stress. Conversely, genetic loss of MAPT increased lysosomal degradative capacity and accumulation of extracellular tau aggregates within acidic compartments, supporting a cell-intrinsic role for endogenous tau in regulating microglial degradative function. Pharmacologic enhancement of the autophagy lysosome pathway in MAPT IVS10+16 microglia increased proteolytic activity and improved tau handling. Together, these findings reveal a reciprocal relationship between tau and microglial lysosome function and identify degradative capacity as a modifiable component of the microglial response to tau pathology.

neuroscience↗

bioRxiv2026

The NORAD-pumilio regulatory axis links lncRNA dysregulation to tau propagation-associated phenotypes

Long non-coding RNAs (lncRNAs) are increasingly implicated in neurodegenerative disease, yet their roles in tauopathy remain poorly understood. Here, we defined the lncRNA landscape across iPSC-derived neurons, astrocytes, and microglia harboring the frontotemporal dementia-associated MAPT IVS10+16 mutation and investigated how lncRNA dysregulation interfaces with tau pathology. Transcriptomic analyses revealed extensive cell-type specific lncRNA expression changes, with neurons exhibiting the greatest degree of mutation-associated remodeling. Comparative analyses with MAPT IVS10+16 patient brain tissue identified NORAD and MIR22HG as lncRNAs significantly dysregulated across all three cell types and human brains. NORAD was also altered in Alzheimers disease and Parkinsons disease brains, suggesting a broader role in neurodegenerative disease. Mechanistically, NORAD-associated protein networks converged on pathways related to RNA regulation, cytoskeletal organization, proteostasis, and tau interaction networks. Given the established role of NORAD in regulating PUM1 and PUM2 RNA-binding (pumilio) proteins, we examined the NORAD-pumilio axis and identified enrichment of pumilio-associated pathways linked to autophagy, endocytosis, proteostasis, and cytoskeletal regulation. NORAD depletion reduced tau seeding and uptake, whereas functional depletion of PUM1 or PUM2 increased both processes, supporting an antagonistic relationship between NORAD and pumilio signaling in modulation of tau aggregation. Together, these findings identify widespread lncRNA dysregulation across neural cell types in the setting of a MAPT mutation and nominate the NORAD-pumilio axis as a regulatory pathway linking RNA homeostasis and tau propagation biology.

neuroscience↗

bioRxiv2025

Ms4a4a deficiency ameliorates plaque pathology in a mouse model of amyloid accumulation

Genome-wide association studies for Alzheimer disease (AD) risk have identified a number of genes enriched in microglia, including MS4A4A. Common variants in MS4A4A influence AD risk, MS4A4A expression, TREM2 signaling, and a specific microglial transcriptional state, though the exact role of MS4A4A in AD remains unclear. Using a mouse model of amyloid beta (A{beta}) accumulation (5xFAD), we examined the impact of Ms4a4a loss on A{beta} pathology. Before A{beta} accumulation, Ms4a4a loss reduces steady-state A{beta} levels and shortens A{beta} half-life in brain interstitial fluid. In aged 5xFAD Ms4a4a-deficient mice, plaques are more compact with reduced overall plaque burden. Microglia lacking Ms4a4a are more pro-inflammatory and produce more MMP-9, which may promote degradation of A{beta} and A{beta} fibrils. Human subjects that carry a variant near MS4A4A (rs1582763) that confers resilience to AD also exhibit significantly elevated levels of MMP-9 in their cerebrospinal fluid. Together, our results suggest that loss of Ms4a4a improves A{beta} pathology by altering A{beta} clearance, offering insights for therapeutic interventions in AD.

neuroscience↗

bioRxiv2021

STAT3 expression in dendritic cells protects mice from colitis by a gut microbiome-dependent mechanism

An imbalance in gut homeostasis results in local and systemic pathogenesis. It is still not well-understood how the immune system interacts with the gut microbiome and maintains a delicate balance. Here, we utilized a mouse model in which STAT3 expression is deleted in CD11c+ (i.e., dendritic) cells (STAT3 cKO); these mice developed an ulcerative colitis-like disease, colon carcinoma and myelodysplastic syndrome-like disease. Circulating IgE levels in STAT3 cKO mice were significantly elevated. The gut microbiome was indispensable for the observed pathogenesis, as treatment with broad-spectrum antibiotics or cross-fostering STAT3 cKO pups with mothers harboring a different microbiome prevented disease development. Gut microbiome analyses suggested that decreased commensal bacteria and increased pathogenic bacteria most likely contributed to disease. Our data suggest that STAT3 controls the manifestation of inflammation in the gut caused by the microbiome. Therefore, we conclude that a deficiency of STAT3 in DCs is sufficient to trigger uncontrolled inflammation and the development of inflammatory bowel disease.

immunology↗