Research Bldg 17, 4.212F
Route: 0620 | Tel: (409) 747-4559 | sagaikwa@utmb.edu
Research ExpertsLab Website: gaikwadlab.org | PubMed

Education and Training

I study why neurons lose the ability to repair their own DNA decades before Alzheimer's disease becomes visible, and I build therapies aimed at that earliest window. My lab combines human postmortem brain, mouse models, iPSC-derived neurons, and large single-nucleus transcriptomic datasets, with funding from the NIH and the Alzheimer's Association.

Research Overview

Alzheimer's disease is usually described as a disease of protein aggregation. Our work argues that the failure of DNA repair comes first. In vulnerable neurons, the chromatin protein HMGB1 leaves the nucleus long before tau tangles or amyloid plaques appear. Without nuclear HMGB1, the non-homologous end joining (NHEJ) machinery that repairs double-strand breaks begins to fail. Damage accumulates, neurons enter a senescent state that releases inflammatory signals into surrounding tissue, and amyloid and tau pathology follow.

The BRAIN Lab (Brain Repair, Aging and Inflammation in Neurodegeneration) tests that sequence directly across four systems: human postmortem brain sampled across Braak stages of disease progression, mouse models of Alzheimer's disease and tauopathy, neurons derived from human induced pluripotent stem cells (iPSCs), and single-nucleus transcriptomic atlases spanning more than one million nuclei from human Alzheimer's brain tissue. Our aim is to convert that mechanism into treatments that can be given early, safely, and without invasive delivery.

Research themes

Nuclear HMGB1 loss as the earliest event in Alzheimer's disease. We propose a "Phase 0" of Alzheimer's disease: a window that precedes any measurable tau or amyloid pathology, in which the earliest damage is already underway. Hyperacetylation of HMGB1, driven by p25/Cdk5-mediated inhibition of the deacetylases HDAC1 and SIRT1, strips the protein from the nucleus. NHEJ capacity drops, double-strand breaks accumulate, and the resulting damage feeds back on repair. This project is a collaboration with Drs. Partha Sarkar, Xiaoyong Bao, and William Russell, together with the Department of Biostatistics and Data Science at UTMB.

Senescence and inflammation in HIV-associated neurocognitive disorder. People living with HIV develop cognitive decline at rates and ages that look like accelerated brain aging, even on suppressive therapy. We are testing whether the same HMGB1–senescence axis operates in the NeuroHIV setting, and whether it is druggable there. This project is supported by an NIMH R21 in collaboration with Drs. Eliseo Eugenin and Janice Endsley.

Senolytic CAR-T therapy for neurodegeneration. Senescent cells accumulate in the aging brain, sustain chronic neuroinflammation, and contribute to progression of Alzheimer's disease. We are engineering chimeric antigen receptor T (CAR-T) cells directed against surface markers of senescent cells in order to clear that burden and slow cognitive decline. This work is supported by a UTMB Pepper OAIC pilot award.

Join the Lab
We welcome inquiries from prospective Ph.D. students and postdoctoral fellows. Please email a CV, a brief statement of research interests, and contact information for three references to sagaikwa@utmb.edu. Rotation students in the Neuroscience Graduate Program are also encouraged to get in touch.

Research Support
National Institutes of Health (NIH)
Alzheimer's Association
UTMB Claude D. Pepper Older Americans Independence Center (OAIC) Pilot Award
UTMB Early Faculty Research Award

Selected Publications

Gaikwad S, Almeida GJ, Darby NT, Calderon T, Ramirez AG, Hughes DC, Patel DI. Therapeutic Yoga Enhances Neuroplasticity and Metabolic Regulation Through Elevated Plasma Brain-Derived Neurotrophic Factor (BDNF) and Ghrelin in a Heterogeneous Cancer Survivor Population. Integr Cancer Ther. 2025;24:15347354251385573. Epub 20251023. doi: 10.1177/15347354251385573. PubMed PMID: 41128015; PMCID: PMC12559641.

†, Gaikwad S†, Tsai CL, Smith C, Zhang N, Bush K, Chakraborty A, Yuan S, Choudhary S, Keene CD, Ellerby LM, Hazra TK, La Spada AR, Wairkar YP, Ashizawa T, Tainer JA, Pandita TK, Thompson LM, Sarkar PS. Huntingtin preserves mitochondrial genome integrity in neurons, which is impaired in Huntington's disease. bioRxiv. 2025. Epub 20250724. doi: 10.1101/2025.07.24.666629. PubMed PMID: 40777236; PMCID: PMC12330591. †Co-first authors.

†, Gaikwad S†, Bush K, Zhang N, Pandita RK, Tsai CL, Smith C, Pandlebury DF, Leonard F, Nie L, Tao A, Russell W, Yuan S, Choudhary S, Ramos KS, Elferink C, Wairkar YP, Tainer JA, Thompson LM, Pandita TK, Sarkar PS. Chromatin remodeler BRG1 recruits huntingtin to repair DNA double-strand breaks in neurons. bioRxiv. 2024. Epub 20240920. doi: 10.1101/2024.09.19.613927. PubMed PMID: 39345557; PMCID: PMC11429940. †Co-first authors.

Gaikwad S, Senapati S, Haque MA, Kayed R. Senescence, brain inflammation, and oligomeric tau drive cognitive decline in Alzheimer's disease: Evidence from clinical and preclinical studies. Alzheimers Dement. 2024;20(1):709–27. Epub 20231009. doi: 10.1002/alz.13490. PubMed PMID: 37814508; PMCID: PMC10841264.

Gaikwad S, Puangmalai N, Sonawane M, Montalbano M, Price R, Iyer MS, Ray A, Moreno S, Kayed R. Nasal tau immunotherapy clears intracellular tau pathology and improves cognitive functions in aged tauopathy mice. Sci Transl Med. 2024;16(754):eadj5958. Epub 20240703. doi: 10.1126/scitranslmed.adj5958. PubMed PMID: 38959324.

Gaikwad S, Montalbano M, Bhuyan A, Garcia S, McAllen S, Sonawane M, Jerez C, Zhao Y, Kayed R. Lysine 63-linked ubiquitination of tau oligomers contributes to the pathogenesis of Alzheimer's disease. J Biol Chem. 2022;298(4):101766. Epub 20220222. doi: 10.1016/j.jbc.2022.101766. PubMed PMID: 35202653; PMCID: PMC8942844.

Gaikwad S, Puangmalai N, Bittar A, Montalbano M, Garcia S, McAllen S, Bhatt N, Sonawane M, Sengupta U, Kayed R. Tau oligomer induced HMGB1 release contributes to cellular senescence and neuropathology linked to Alzheimer's disease and frontotemporal dementia. Cell Rep. 2021;36(3):109419. doi: 10.1016/j.celrep.2021.109419. PubMed PMID: 34289368; PMCID: PMC8341760.

Gaikwad S, Ventura F, McAllen S, Ellsworth A, Garcia S, Kayed R. Internalization mechanisms of brain-derived tau oligomers from patients with Alzheimer's disease, progressive supranuclear palsy and dementia with Lewy bodies. Cell Death Dis. 2020;11(5):314. Epub 20200504. doi: 10.1038/s41419-020-2503-3. PubMed PMID: 32366836; PMCID: PMC7198578.

Gaikwad S, Saswat T, Chattopadhyay S, Das BK, Tripathy R, Ravindran B. Cytokine Signature Associated with Disease Severity in Dengue. Viruses. 2019;11(1). Epub 20190108. doi: 10.3390/v11010034. PubMed PMID: 30626045; PMCID: PMC6357178.

Gaikwad S, Challagundla N, Nivsarkar M, Agrawal-Rajput R. Spleen tyrosine kinase inhibition ameliorates airway inflammation through modulation of NLRP3 inflammosome and Th17/Treg axis. Int Immunopharmacol. 2018;54:375–84. Epub 20171205. doi: 10.1016/j.intimp.2017.11.026. PubMed PMID: 29202301.

Gaikwad S. The biological clock: Future of neurological disorders therapy. Neural Regen Res. 2018;13(3):567–8. doi: 10.4103/1673-5374.228764. PubMed PMID: 29623946; PMCID: PMC5900524.

Gaikwad S, Patel D, Agrawal-Rajput R. CD40 Negatively Regulates ATP-TLR4-Activated Inflammasome in Microglia. Cell Mol Neurobiol. 2017;37(2):351–9. Epub 20160310. doi: 10.1007/s10571-016-0358-z. PubMed PMID: 26961545; PMCID: PMC11482137.

Gaikwad S, Agrawal-Rajput R. Berberine induces neuronal differentiation through inhibition of cancer stemness and epithelial-mesenchymal transition in neuroblastoma cells. Phytomedicine. 2016;23(7):736–44. Epub 20160413. doi: 10.1016/j.phymed.2016.03.013. PubMed PMID: 27235712.

Gaikwad S, Naveen C, Agrawal-Rajput R. Toll-like receptor-4 antagonism mediates benefits during neuroinflammation. Neural Regen Res. 2016;11(4):552–3. doi: 10.4103/1673-5374.180732. PubMed PMID: 27212907; PMCID: PMC4870903.

Gaikwad S, Agrawal-Rajput R. Lipopolysaccharide from Rhodobacter sphaeroides Attenuates Microglia-Mediated Inflammation and Phagocytosis and Directs Regulatory T Cell Response. Int J Inflam. 2015;2015:361326. Epub 20150917. doi: 10.1155/2015/361326. PubMed PMID: 26457222; PMCID: PMC4589630.