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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

a-syn promotes neurodegeneration and neuro-inflammation via TLR’s and involves microglial responses via LRRK2

Immunotherapy targeting a-syn and Abeta ameliorates neurodegeneration in models of DLB and AD

Synergistic combinatorial therapeutics targeting a-syn and inflammation in DLB/PD models

MAPK p38 plays a dual role mediating neuro-inflammatory and synaptic degeneration in DLB and in vivo models

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

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