Molecular Neuropathology Unit

Eliezer Masliah, M.D., Unit Head

The main objective of the Molecular Neuropathology Unit (MNU) at LNG is to harness the immune system to better understand the mechanisms of neurodegeneration and to develop therapies for synucleinopathies of the aging population. Although traditionally dementia with Lewy bodies (DLB), idiopathic Parkinson’s disease (PD), PD dementia (PDD) and Multiple System Atrophy (MSA) are considered examples of typical synucleinopathies, recently we have found that a-synuclein (a-syn) also accumulates in selected brain regions in patients with Alzheimer’s disease (AD). a-synuclein is a small neuronal protein (140 aa) that plays a role in synaptic plasticity and lymphocyte maturation. The MNU investigates the cross-talk between a-syn and the innate and adaptive immune responses and how they might mediate neuro-inflammation, synaptic damage and ultimately functional deficits in AD, DLB and PD. For this purpose we have developed novel immunotherapeutical, gene therapy and small molecules approaches targeting the interactions between the immune system and a-syn in these neurodegenerative disorders. We utilize state of the art in vivo and in vitro models of AD, DLB and PD and focus in the neuropathological alterations and response to therapeutics. Targeting the a-syn immune mediated responses might be of critical importance both for developing new treatments for DLB/PD and AD. Together, AD and DLB are part of the main mission of the NIA in the context of the US National Plan to Address AD.

Portfolio/Research Areas

• Neuropathological alterations in AD, DLB, PD, MSA and other neurodegenerative disorders
• Interactions between a-syn and the innate immune system mediated by TLR’s and kinases including LRRK2 and MAPK
• Role of a-syn accumulation and cell to cell propagation in mediating neuro-inflammation, synaptic damage and ultimately functional deficits
• Mechanisms through which adaptive immune responses in particular CNS infiltration by T cells mediates neuro-inflammation and neurodegeneration in DLB/PD
• Novel immunotherapeutical, gene therapy and small molecules treatments targeting the interactions between the immune system and a-syn in these neurodegenerative disorders.
• Combinatorial therapeutics for AD, DLB and PD.
• Role of aging in mediating a-syn and the immune system alterations and if anti-aging therapies might revert this process.

Key Findings and Publications

• Aging accelerates a-syn accumulation and adaptive T cells responses in DLB and animal models that in turn activate microglia to promote neurodegeneration via TLR’s and a novel pathway that includes CSF2R
• T cells infiltrate the CNS in DLB/PD and in vivo models, including CD4, CD8 and NKT cells that secrete CSF2
• A-syn promotes neurodegeneration and neuro-inflammation via TLR’s and involves microglial responses via LRRK2, blocking LRKK2 ameliorates behavioral deficits and neuroinflammation in models of DLB/PD
• LRRK2 phosphorylates the transcription factor NFAT2c in microglia that in turns mediated neuroinflammatory responses, blocking NFAT2c abrogates a-syn mediated neurotoxicity
• Immunotherapy targeting a-syn and Abeta ameliorates neurodegeneration in models of DLB and AD
• Combinatorial DLB/PD immunotherapeutics targeting various a-syn epitopes can be developed using DNA vaccine technology
• MAPK p38 plays a dual role mediating neuro-inflammatory and synaptic degeneration in DLB and in vivo models
• P38alpha is expressed in microglia and increased in DLB/PD, P38gamma is present in the synapses and is mis-localized to the Lewy bodies in DLB/PD, blocking the p38alpha pathway with small molecules reduces neuroinflammation in models of DLB/PD but also ameliorates neurodegeneration by shifting the location of p38gamma back to the synapses
• Synergistic combinatorial therapeutics targeting a-syn and inflammation in DLB/PD models includes combination of immunotherapy and molecules blocking TLR2, LRRK2, CSF2R, NFAT2c
• A-syn and Sars-CoV2 proteins might interact and trigger beuroinflammation via TLR’s

Recent Publications

El-Agnaf O, Overk C, Rockenstein E, Mante M, Florio J, Adame A, Vaikath N, Majbour N, Lee SJ, Kim C, Masliah E, Rissman RA. Differential effects of immunotherapy with antibodies targeting alpha- synuclein oligomers and fibrils in a transgenic model of synucleinopathy. Neurobiol Dis. 2017;104:85-96. PMC:5954414

Kim C, Spencer B, Rockenstein E, Yamakado H, Mante M, Adame A, Fields JA, Masliah D, Iba M, Lee HJ, Rissman RA, Lee SJ,Masliah E., Immunotherapy targeting toll-like receptor 2 alleviates neurodegeneration in models of synucleinopathy by modulating α-synuclein transmission and neuroinflammation. Mol Neurodegener. 2018 Aug 9;13(1):43. doi: 10.1186/s13024-018-0276-2. PMC6085656.

Rockenstein E, Ostroff G, Dikengil F, Rus F, Mante M, Florio J, Adame A, Trinh I, Kim C, Overk C, Masliah E, Rissman RA. Combined Active Humoral and Cellular Immunization Approaches for the Treatment of Synucleinopathies. J Neurosci. 2018 Jan 24;38(4):1000-1014. Epub 2017 Dec 15. PMC5783958.

Bae EJ, Kim DK, Kim C, Mante M, Adame A, Rockenstein E, Ulusoy A, Klinkenberg M, Jeong GR, Bae JR, Lee C, Lee HJ, Lee BD, Di Monte DA, Masliah E, Lee SJ. LRRK2 kinase regulates α-synuclein propagation via RAB35 phosphorylation. Nat Commun. 2018 Aug 27;9(1):3465. doi: 10.1038/s41467-018-05958-z. PMID: 30150626

Spencer B, Trinh I, Rockenstein E, Mante M, Florio J, Adame A, El-Agnaf OMA, Kim C, Masliah E, Rissman RA. Systemic peptide mediated delivery of an siRNA targeting α-syn in the CNS ameliorates the neurodegenerative process in a transgenic model of Lewy body disease. Neurobiol Dis. 2019 Jul;127:163-177. doi: 10.1016/j.nbd.2019.03.001. Epub 2019 Mar 5. PMID: 30849508

Gerez JA, Prymaczok NC, Rockenstein E, Herrmann US, Schwarz P, Adame A, Enchev RI, Courtheoux T, Boersema PJ, Riek R, Peter M, Aguzzi A, Masliah E, Picotti P. A cullin-RING ubiquitin ligase targets exogenous α-synuclein and inhibits Lewy body-like pathology. Sci Transl Med. 2019 Jun 5;11(495). pii: eaau6722. doi: 10.1126/scitranslmed.aau6722. PMID: 31167929

Mandler M, Rockenstein E, Overk C, Mante M, Florio J, Adame A, Kim C, Santic R, Schneeberger A, Mattner F, Schmidhuber S, Galabova G, Spencer B, Masliah E, Rissman RA. Effects of single and combined immunotherapy approach targeting amyloid β protein and α-synuclein in a dementia with Lewy bodies-like model. Alzheimers Dement. 2019 Aug 1. pii: S1552-5260(19)30071-8. PMID:31378574

Kwon S, Iba M, Masliah E, Kim C. Targeting Microglial and Neuronal Toll-like Receptor 2 in Synucleinopathies. Exp Neurobiol. 2019 Oct 31;28(5):547-553. doi: 10.5607/en.2019.28.5.547. PMID: 3169854

Iba M, Kim C, Florio J, Mante M, Adame A, Rockenstein E, Kwon S, Rissman R, Masliah E. Role of Alterations in Protein Kinase p38γ in the Pathogenesis of the Synaptic Pathology in Dementia With Lewy Bodies and α-Synuclein Transgenic Models. Front Neurosci. 2020 Mar 31;14:286. doi: 10.3389/fnins.2020.00286. eCollection 2020. PMC7138105

Iba M, Kim C, Sallin M, Kwon S, Verma A, Overk C, Rissman RA, Sen R, Sen JM, Masliah E. Neuroinflammation is associated with infiltration of T cells in Lewy body disease and α-synuclein transgenic models. J Neuroinflammation. 17(1):214 2020. [PMID: 32680537] PMC7368752.

Kim C, Beilina A, Smith N, Li Y, Kim M, Kumaran R, Kaganovich A, Mamais A, Adame A, Iba M, Kwon S, Lee WJ, Shin SJ, Rissman RA, You S, Lee SJ, Singleton AB, Cookson MR, Masliah E. LRRK2 mediates microglial neurotoxicity via NFATc2 in rodent models of synucleinopathies. Sci Transl Med. 12(565) 2020. [PMID: 33055242] PMC8100991.

Kwon S, Iba M, Kim C, Masliah E. Immunotherapies for Aging-Related Neurodegenerative Diseases-Emerging Perspectives and New Targets. Neurotherapeutics. 2020 Apr 28:1-20. doi: 10.1007/s13311-020-00853-2. PMC7222955

Marschallinger J, Altendorfer B, Rockenstein E, Holztrattner M, Garnweidner-Raith J, Pillichshammer N, Leister I, Hutter-Paier B, Strempfl K, Unger MS, Chishty M, Felder T, Johnson M, Attems J, Masliah E, Aigner L. The Leukotriene Receptor Antagonist Montelukast Reduces Alpha-Synuclein Load and Restores Memory in an Animal Model of Dementia with Lewy Bodies. Neurotherapeutics. 17(3):1061-1074 2020. [PMID: 32072462] PMC7609773.

Monzio Compagnoni G, Di Fonzo A, Corti S, Comi GP, Bresolin N, Masliah E. The Role of Mitochondria in Neurodegenerative Diseases: the Lesson from Alzheimer's Disease and Parkinson's Disease. Mol Neurobiol. 57(7):2959-2980 2020. [PMID: 32445085].

Ngolab J, Trinh I, Rockenstein E, Mante M, Florio J, Trejo M, Masliah D, Adame A, Masliah E, Rissman RA. Correction to: Brain-derived exosomes from dementia with Lewy bodies propagate α-synuclein pathology. Acta Neuropathol Commun. 8(1):123 2020. [PMID: 32753049] PMC7405419.

Regensburger M, Stemick J, Masliah E, Kohl Z, Winner B. Intracellular A53T Mutant α-Synuclein Impairs Adult Hippocampal Newborn Neuron Integration. Front Cell Dev Biol. 8:561963 2020. [PMID: 33262984] PMC7686440.

Saez-Atienzar S, Masliah E. Cellular senescence and Alzheimer disease: the egg and the chicken scenario. Nat Rev Neurosci. 21(8):433-444 2020. [PMID: 32601397].

Waragai M, Ho G, Takamatsu Y, Wada R, Sugama S, Takenouchi T, Masliah E, Hashimoto M. Adiponectin Paradox in Alzheimer's Disease; Relevance to Amyloidogenic Evolvability? Front Endocrinol (Lausanne). 11:108 2020. [PMID: 32194507] PMC7065259.

Kim C, Kwon S, Iba M, Spencer B, Rockenstein E, Mante M, Adame A, Shin SJ, Fields JA, Rissman RA, Lee SJ, Masliah E. Effects of innate immune receptor stimulation on extracellular α-synuclein uptake and degradation by brain resident cells. Exp Mol Med. 53(2):281-290 2021. [PMID: 33594256] PMC8080790.

Lee MH, Perl DP, Nair G, Li W, Maric D, Murray H, Dodd SJ, Koretsky AP, Watts JA, Cheung V, Masliah E, Horkayne-Szakaly I, Jones R, Stram MN, Moncur J, Hefti M, Folkerth RD, Nath A. Microvascular Injury in the Brains of Patients with Covid-19. N Engl J Med. 384(5):481-483 2021. [PMID: 33378608] PMC7787217.

Ngolab J, Canchi S, Rasool S, Elmaarouf A, Thomas K, Sarsoza F, Grundman J, Mante M, Florio J, Nandankar N, Korouri S, Zago W, Masliah E, Rissman RA. Mutant three-repeat tau expression initiates retinal ganglion cell death through Caspase-2. Neurobiol Dis. 152:105277 2021. [PMID: 33516874] PMC8373010.

Roshanbin S, Aniszewska A, Gumucio A, Masliah E, Erlandsson A, Bergström J, Ingelsson M, Ekmark-Lewén S. Age-related increase of alpha-synuclein oligomers is associated with motor disturbances in L61 transgenic mice. Neurobiol Aging. 101:207-220 2021. [PMID: 33639338].

Torres ERS, Stanojlovic M, Zelikowsky M, Bonsberger J, Hean S, Mulligan C, Baldauf L, Fleming S, Masliah E, Chesselet MF, Fanselow MS, Richter F. Alpha-synuclein pathology, microgliosis, and parvalbumin neuron loss in the amygdala associated with enhanced fear in the Thy1-aSyn model of Parkinson's disease. Neurobiol Dis. 158:105478 2021. [PMID: 34390837] PMC8447919.

Kim C, Hovakimyan A, Zagorski K, Antonyan T, Petrushina I, Davtyan H, Chailyan G, Hasselmann J, Iba M, Adame A, Rockenstein E, Szabo M, Blurton-Jones M, Cribbs DH, Ghochikyan A, Masliah E, Agadjanyan MG. Efficacy and immunogenicity of MultiTEP-based DNA vaccines targeting human α-synuclein: prelude for IND enabling studies. NPJ Vaccines. 7(1):1 2022. [PMID: 35013319] PMC8748802.

Spencer B, Rissman RA, Overk C, Masliah E. Novel Brain-Penetrating Single Chain Antibodies Directed Against 3RTau for the Treatment of Alzheimer's Disease and Related Dementias. Methods Mol Biol. 2383:447-457 2022. [PMID: 34766306].