Research Faculty

Address
630 West 168th Street
P&S 12-461
New York, NY 10032

Phone: 212-305-8790
Fax: 212-342-0119

ked2115@columbia.edu
Education and Training
Ph.D University of Cambridge (UK) 1991. Lab of Sydney Brenner

Affiliations
Integrated Program
MD-PhD Program
Neurobiology & Behavior
Taub Institute
Psychiatry


Collaborations
Gil Di Paolo, Scott Small
Karen Duff, Ph.D.
Professor of Pathology & Cell Biology
Research Summary

In general, we are exploring what goes wrong in the brains of patients with neurodegenerative diseases, especially Alzheimer’s disease (AD) and Frontal Temporal lobe Degeneration linked to tauopathy (FTD-tau) with the overall aim of identifying therapeutic approaches that may be beneficial for the treatment, or prevention of these diseases. Given our broad interest in neurodegenerative disease etiology and the insights to be gained by studying different diseases my lab has created various mouse models for the study of AD (amyloid accumulation), tauopathies and synucleinopathies. These models have facilitated the study of many aspects of pathogenesis from how the disease propagates through the brain, to imaging studies allowing the examination of structural and functional changes in the brain in living animals, to the identification of relevant druggable pathways and the testing of drugs. Our current interests are fourfold- the propagation of disease through the brain, the impact of ApoE4 on disease risk, the impact and restoration of functional clearance mechanisms and the basis and manipulation of memory deficits using optogenetic and brain stimulation techniques.

Service Activities

Regular member of NIH study sections (previous Chair, CDIN)
Reviewer – foundation grants
Reviewer- journals.
Medical advisory council- AFTD

Selected Publications

Please click the PubMed link below:
Current Projects

There are currently four projects underway in the lab.

1). One recent undertaking is to identify new pathways impacted by ApoE genotype that might explain why inheritance of ApoE4 allele increases risk for AD using a multi-omics approach (transcriptomics, lipidomics and metabolomics) on the same, pathology free human or ApoE targeted mouse brain tissue.

2). As the brains of AD patients often show multiple pathologies and accumulate several different types of potentially neurotoxic misfolded proteins including Abeta, tau, synuclein and TDP-43, we are currently focused on understanding the role of misfolded protein clearance pathways (mainly autophagy and UPS clearance) in disease etiology. In addition, as clinical trials using Abeta immunotherapy have suggested that reducing Abeta/amyloid in mild-moderate AD patients has no effect on their tauopathy, which continues to propagate, it would seem that drugs aimed at clearing all misfolded protein types from the brain would be beneficial.

3). It also seems likely that we will need to intervene very early in the disease, perhaps prophylactically, and at this time, very little is known of disease initiation and the earliest stages of propagation as most of the animal models that we, and others have generated do not accurately model the spatial and temporal sequence of the disease. Our more recent work modeling AD tauopathy using wild-type genomic (BAC derived) tau constructs has aimed to more faithfully replicate spatio-temporal aspects of tauopathy in AD, and current work aims to explore cellular and circuit vulnerability that defines a particular neurodegenerative disease. We have recently created a line of mice that models the earliest Braak stages of AD, when tauopathy is restricted to the entorhinal cortex (EC) and hippocampus. These mice, and a parallel line that expresses APP are being studied for spatial and temporal correlations of pathology and functional outcomes. One of the most significant findings from the mice so far is that tauopathy can spread through the brain along synaptically connected networks, and the observation that tau molecules can be transmitted from cell to cell, in vivo. Additionally, our collaborator Scott Small has shown using fMRI imaging that dysfunction can spread to downstream brain regions, and that Abeta can potentiate the toxicity of tau expressed in the EC. Understanding the mechanisms involved in propagation, the impact on anatomically connected circuits and the relationship to functional decline determined by functional imaging and cognitive performance are the major directions for the lab.

4). We have a new project underway to look at the neurobiology of memory and learning and how it becomes dysfunctional in AD and FTD. This project also aims to look at how increasing neural activity may be harnessed to prevent cognitive decline, or even improve memory recall.


Honors and Awards

2006 - Potamkin prize 2006
2010 - Speaker, NIH director’s Wednesday Afternoon Lecture

Committees , Council, and Professional Society Memberships

SFN
MAC AFTD

Keywords

Alzheimer’s, neurodegenerative, tauopathies, tau, amyloid, propagation, spread, apoE, neural activity, functional decline, cognitive decline


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