Matthew P. Frosch, MD, PhD

Frosch Lab

“Development and characterization of animal models of human neurodegenerative diseases...”

Overview

Matthew P. Frosch, MD, PhD

Lawrence J. Henderson Associate Professor of Pathology and
Health Sciences & Technology, Harvard Medical School
Director, C.S. Kubik Laboratory for Neuropathology,
Massachusetts General Hospital
MassGeneral Institute for Neurodegenerative Diseases (MIND)

MassGeneral Institute for Neurodegenerative Diseases (MIND)
Massachusetts General Hospital
114 16th Street, Room 2700
Charlestown, MA 02129
Phone: 617-726-5156
Fax: 617-724-1813
Email: mfrosch@partners.org

Overview

My lab aims to understand cerebral amyloid angiopathy (CAA), using mouse models and human tissue. In this disease, the peptide Aβ deposits in the walls of blood vessels and is associated with risk of hemorrhage (‘lobar hemorrhages’). This peptide is the same material that forms the plaques of Alzheimer disease, and nearly all patients with Alzheimer disease have pathologic evidence of CAA as well. CAA also occurs in the absence of histologic evidence of Alzheimer disease, and can present with hemorrhages or with cognitive changes. In clinicopathologic studies, we have found that this latter presentation is associated with the presence of an inflammatory response, often containing giant cells. This subset of patients can have dramatic recoveries of cognitive function after immunosuppressive therapy.


We are interested in the sequence of events by which Aβ is deposited in blood vessels, what factors determine the distribution of involvement, what the consequences are for the cells of the vessel and how this material can respond to therapeutic interventions that have been shown to alter Aβ deposits in the brain (immunotherapy, gamma-secretase inhibitors). Current topics of particular interest involve the timing of oxidative stress induction by CAA, expression of matrix degrading enzymes such as MMP-9 and induction of apoptosis in vascular smooth muscle cells. We use serial in vivo multiphoton imaging with specific probes for these various processes and link the spatial and temporal distribution of the pathologic changes with the development of CAA. We complement these studies with immunohistochemistry, image reconstruction and laser capture microdissection to define alterations in gene expression that occur in smooth muscle cells in the proximity of amyloid deposits of CAA. Finally, our observations in mouse models of CAA can be validated through the use of human autopsy tissue, collected through the Massachusetts Alzheimer Disease Research Center Neuropathology Core.


I also work with a range of collaborators to understand the relationship between neuropathologic findings in the setting of disease – including Alzheimer disease, Parkinson disease, Amyotrophic Lateral Sclerosis and others – and other biochemical or functional markers of disease. These studies include advancing imaging methods (DTI, OCT and others) as well as various genetic studies (deep sequencing as well as GWAS), cell biology and structural biology.

 

Group Members

Laboratory Members

Isabel Costantino, Tech II
Nehal Patel, Tech II

Harvard NeuroDiscovery Center Staff 

Charles Vanderburg, PhD
Ozge Casgal-Getkin, Tech II

Research Projects

The current major research emphasis in my lab focuses on the development of cerebral amyloid angiopathy (CAA) in mouse models. In this disease, the peptide A-beta deposits in the walls of blood vessels and is associated with risk of hemorrhage ('lobar hemorrhages'). This peptide is the same material that forms the plaques of Alzheimer disease, and nearly all patients with Alzheimer disease have pathologic evidence of CAA as well. CAA also occurs in the absence of histologic evidence of Alzheimer disease, and can present with hemorrhages or with cognitive changes.

In a recent clinicopathologic study, we have found that this latter presentation is associated with the presence of an inflammatory response, often containing giant cells. This subset of patients can have dramatic recoveries of cognitive function after immunosuppressive therapy. For these reasons, we are interested in learning what the sequence of events is by which the A-beta is deposited in blood vessels, what factors determine the distribution of involvement, what the consequences are for the cells of the vessel and how this material can respond to therapeutic interventions that have been shown to alter A-beta deposits in the brain.

We are pursuing these studies using multiphoton imaging as applied both ex vivo to fixed brains and in vivo through a glass window placed in the skull. These investigations are to be complemented by a series of immunohistochemical studies and image reconstruction to match the vessel structure and integrity with the 3-dimensional image generated using the multiphoton approach. We also aim to use laser capture microdissection to define alterations in gene expression that occur in smooth muscle cells in the proximity of amyloid deposits of CAA.

Research Positions

Request a list of currently open positions at MIND mghneurologyjobs@partners.org.

Read about and apply for residency, fellowship and observership programs in Pathology at http://www.massgeneral.org/pathology/training/ or in Neurology at http://www.massgeneral.org/neurology/education/.

Apply for temporary positions (summer interns)through the Bulfinch Temporary Service Web site at http://www.massgeneral.org/careers/temporary.aspx. Search for all opportunities using ID# 2200484.

All applicants should register with the Mass General Careers Web site at http://www.massgeneral.org/careers/viewall.aspx.

Selected Publications

Bibliography of Matthew P. Frosch via PubMed

Zhao L, Arbel-Ornath M, Wang X, Betensky RA, Greenberg SM, Frosch MP, Bacskai BJ. Matrix metalloproteinase 9-mediated intracerebral hemorrhage induced by cerebral amyloid angiopathy. Neurobiol Aging. 2015;36(11):2963-71.

Arbel-Ornath M, Hudry E, Eikermann-Haerter K, Hou S, Gregory JL, Zhao L, Betensky RA, Frosch MP, Greenberg SM, Bacskai BJ. Interstitial fluid drainage is impaired in ischemic stroke and Alzheimer's disease mouse models.  Acta Neuropathol. 2013;126(3):353-64.

Greenberg CH, Frosch MP, Goldstein JN, Rosand J, Greenberg SM. 3Modeling intracerebral hemorrhage growth and response to anticoagulation. PLoS One. 2012;7(10):e48458.
 
Gregory JL, Prada CM, Fine SJ, Garcia-Alloza M, Betensky RA, Arbel-Ornath M, Greenberg SM, Bacskai BJ, Frosch MP. Reducing available soluble β-amyloid prevents progression of cerebral amyloid angiopathy in transgenic mice. J Neuropathol Exp Neurol. 2012; 71(11):1009-17.

Garcia-Alloza M, Gregory J, Kuchibhotla KV, Fine S, Wei Y, Ayata C, Frosch MP, Greenberg SM, Bacskai BJ. Cerebrovascular lesions induce transient β-amyloid deposition. Brain. 2011;134(Pt 12):3697-707.

Contact

Contact Us

Frosch Laboratory

MassGeneral Institute - Neurodegenerative Disease

114 16th StreetMassachusetts General Hospital, B114-2700 Charlestown, MA 02129
  • Phone: 617-726-5156
  • Fax: 617-724-1813

Email: mfrosch@partners.org

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