Nimansha Jain

MSTP in PhD Training

Program: Neurosciences

Current advisor: David M. Holtzman, MD

Undergraduate university: University of Pennsylvania, 2017

Enrollment year: 2018

Research summary
TREM2 as a therapeutic target in Alzheimer’s Disease

Rare variants contributing to a partial loss of function in TREM2, a cell surface receptor specifically found on microglia in the brain, increase Alzheimer’s Disease (AD) risk by 2 to 4-fold. Previous studies by our group and others have studied the effects of TREM2 deficiency on A β plaques, hypothesized to be an initiator of AD, and found that the loss or reduction of TREM2 function decreased microgliosis surrounding plaques in multiple mouse models and in humans expressing the AD-risk allele, TREM2 R47H. AD has no currently approved disease-modifying therapies and treatments to prevent, delay the onset, or slow the progression are urgently needed. Since the R47H partial-loss-of-function variant of the microglial receptor TREM2 was found to increase risk for AD, it is important to explore this gene as a possible therapeutic target in AD. I am working in the laboratory of Dr. David Holtzman to better understand if increasing TREM2 signaling is protective against AD pathology in the brain within the context of an amyloid model that develops tau tangles.

Graduate publications
Jain N, Lewis CA, Ulrich JD, Holtzman DM. 2023 Chronic TREM2 activation exacerbates Aβ-associated tau seeding and spreading. J Exp Med, 220(1):e20220654.

Seo DO, O’Donnell D, Jain N, Ulrich JD, Herz J, Li Y, Lemieux M, Cheng J, Hu H, Serrano JR, Bao X, Franke E, Karlsson M, Meier M, Deng S, Desai C, Dodiya H, Lelwala-Guruge J, Handley SA, Kipnis J, Sisodia SS, Gordon JI, Holtzman DM. 2023 ApoE isoform- and microbiota-dependent progression of neurodegeneration in a mouse model of tauopathy. Science, 379(6628):eadd1236.

Gratuze M, Schlachetzki JCM, D’Oliveira Albanus R, Jain N, Novotny B, Brase L, Rodriguez L, Mansel C, Kipnis M, O’Brien S, Pasillas MP, Lee C, Manis M, Colonna M, Harari O, Glass CK, Ulrich JD, Holtzman DM. 2022 TREM2-independent microgliosis promotes tau-mediated neurodegeneration in the presence of ApoE4. Neuron, S0896-6273(22):00955-2.

Jain N, Ulrich JD. 2022 TREM2 and microglia exosomes: a potential highway for pathological tau. Mol Neurodegener, 17(1):73.

Diaz-Ortiz ME, Seo Y, Posavi M, Carceles Cordon M, Clark E, Jain N, Charan R, Gallagher MD, Unger TL, Amari N, Skrinak RT, Davila-Rivera R, Brody EM, Han N, Zack R, Van Deerlin VM, Tropea TF, Luk KC, Lee EB, Weintraub D, Chen-Plotkin AS. 2022 GPNMB confers risk for Parkinson’s disease through interaction with α-synuclein. Science, 377(6608):eabk0637.

Gratuze M, Chen Y, Parhizkar S, Jain N, Strickland MR, Serrano JR, Colonna M, Ulrich JD, Holtzman DM. 2021 Activated microglia mitigate Aβ-associated tau seeding and spreading. J Exp Med, 218(8):e20210542.

Leyns CEG, Gratuze M, Narasimhan S, Jain N, Koscal LJ, Jiang H, Manis M, Colonna M, Lee VMY, Ulrich JD, Holtzman DM. 2019 TREM2 function impedes tau seeding in neuritic plaques. Nat Neurosci, 22(8):1217-1222.