2009 Pilot Projects

Description

Cerebral amyloid angiopathy (CAA) is found in approximately one-third of all elderly patients (> 60 years of age) and about 90% of patients with Alzheimer’s Disease (AD).  CAA is a well-recognized cause of brain hemorrhage and is also a known contributor to ischemic stroke and dementia.  Yet, to date only a “possible” or “probable” diagnosis of CAA is achievable without obtaining brain tissue from the patient via biopsy, or at autopsy.

This project provides a basis for a non-invasive method of diagnosing CAA in live patients, to permit the diagnosis of CAA prior to onset of brain hemorrhage; enable critical studies to be performed to conclusively establish and define the contribution of CAA to Alzheimer’s Disease, other forms of dementia, and ischemic stroke; and greatly facilitate the development of desperately needed clinical trials to test promising new CAA therapies that are currently in the research pipeline.

Grants and Awards

“PET tracers for cerebrovascular-specific amyloid imaging”
American Health Assistance Foundation Research Award (Han, PI; Zipfel, Co-Investigator)

Intellectual Property

“Phenoxazine Derivatives and Methods of Use Thereof”; Attorney Docket Number 047563-401187; Inventors: Gregory Zipfel, Henry Han, Robert Mach, Wenhua Chu; Provisional Patent Submitted July 30, 2010. (Patent Pending)

Updated June 2017

Description

Aβ is the major peptide component of amyloid plaque, a hallmark of Alzheimer’s Disease. The investigators hypothesize that the creation of amyloid aggregates begins with the formation of “amyloid seeds,” early aggregations of the Aβ peptide that forms plaques, in the lysosomes of neural cells.

This project investigates a potential mechanism of amyloid-beta (Aβ) aggregation, i.e., the mechanism through which early aggregation of amyloid occurs in lysosomes.

This project will yield vital information about the fundamental mechanisms of Alzheimer’s Disease, including genes that may be critical to plaque formation and may indicate the need for changes in transgenic mouse models for Alzheimer’s Disease. Furthermore, the investigators will use high-throughput screening to identify small molecular compounds that inhibit the formation of amyloid seeds and thereby provide a foundation for drug development.

Grants and Awards

“Develop Screening Assays to Differentiate ApoE Isoforms”
AHAF Grant

“Enhancing Lysosome Biogenesis to Prevent Amyloid Plaque Pathogenesis”NIH/NINDS R21NS082529  (PI, Lee)
This grant proposes to study the role of lysosomal degradation pathways in Aβ and APP metabolism and the development of AD pathology.

“Endocytic Trafficking in Synaptic Amyloid-Beta Generation”
American Health Assistance Foundation (AHAF) A2012151  (PI, Cirrito; Co-PI, Lee)
The goal of this grant is to determine the role for PICALM in endocytosis of APP and subsequent intracellular processing in Alzheimer’s Disease pathogenesis.

“Enhancing Lyosome Biogenesis to Prevent Amyloid Plaque Pathogenesis”
Alzheimer’s Association   ( PI, Diwan; Co-PI, Lee)
The proposal seeks to employ TEFB-mediated lysosomal biogenesis to promote amyloid proteindegradation in neurons, as a strategy to reduce amyloid peptid levels in the brain parenchyma andprevent amyloid plaque deposits.

“Tracking Intracellular pathways to Abeta generation“
NIH/NIA    R21 AG055333 (PI, Lee)
A hallmark of Alzheimer’s disease brains is amyloid plaques composed primarily of amyloid-beta peptide generated and released from affected neurons. Current therapeutic strategies focus on reducing extracellular amyloid-beta but little is known about cellular mechanisms controlling where the peptide is generated in living neurons. In this proposal we will use a novel method we developed to specifically address this question. Results from our studies may lead in the future to better strategies to control Alzheimer’s disease.

Publications

Garai K, Baban B, Frieden C. The Self-association and stability of the ApoE isoforms at low pH: implications for ApoE-lipid interactions. Biochemistry. 50 6356-6364 (2011).

Fuentealba R.A., Zhang J., Liu Q., Kanekiyo T., Hu X., Lee J.-M., LaDu M.J., Bu G.  Low-density lipoprotein receptor-related protein 1 (LRP1) mediates neuronal Ab42 uptake and lysosomal trafficking. PLoS ONE, 5(7):e11884, (2011).

Bero A.W., Yan P., Roh J.H., Cirrito J.R., Stewart F.R., Raichle M.E., Lee J.M., Holtzman D.M., Neuronal activity regulates the regional vulnerability to amyloid-beta deposition. Nat Neurosci, 14(6):750-6, (2011).

Xiao Q., Gil S.C., Yan P., Wang Y., Han S., Gonzales E., Perez R., Cirrito J.R., Lee J.-M.* Role of Phosphatidylinositol Clathrin Assembly Lymphoid-Myeloid Leukemia (PICALM) in intracellular Amyloid Precursor Protein (APP) Processing and Amyloid Plaque Pathogenesis. J Biol Chem, 287(25):21279-89, (2012).

Kraft A., Hu X., Yoon H., Yan P., Zhu A., Xiao Q., Wang Y., Gil S.C., Brown J., Wilhelmsson U., Restivo J.L., Cirrito J.R., Holtzman D.M., Kim J., Pekny M., Lee J.-M.*  Attenuating astrocyte activation accelerates plaque pathogenesis and neurotoxicity in APP/PS1 mice. FASEB J, 27(1):187-98, (2012).

Xiao Q, Yan P, Ma X, Liu H, Perez R, Zhu A, Gonzales E, Tripoli DL, Czerniewski L, Ballabio A, Cirrito JR, Diwan A, Lee JM. Neuronal-Targeted TFEB Accelerates Lysosomal Degradation of APP, Reducing Aβ Generation and Amyloid Plaque Pathogenesis. J Neurosci ;35(35):12137-51, (2015).

Updated June 2017

Description

One of the common features of neurodegenerative diseases such as ALS, Alzheimer’s disease, Parkinson’s disease, and Huntington’s disease is the presence of proteins that are misfolded. Evidence for the misfolded proteins is found in the brain and spinal cord and much research has focused on the adverse consequences of these misfolded proteins for the brain and spinal cord. On the other hand, tissues outside of the nervous system appear mostly unaffected by these same proteins, which are clearly present at similar levels.

Drs. Miller and Weihl are focused on figuring out how the liver handles misfolded SOD1 protein to prevent damage. Misfolded SOD1 causes inherited amyotrophic lateral sclerosis (ALS, also known as Lou Gehrig’s Disease), a disease characterized by progressive weakness, muscle atrophy, loss of ability to speak and swallow, and death from failure of respiratory muscles 3-5 years after the beginning of the disease. Miller and Weihl hypothesize that a substance found in the liver acts to modify SOD1 misfolding and thus ameliorate its toxic effects.

In this project, they will isolate and identify one or more specific liver proteins that inhibit protein folding in these cells. If these factors can be introduced into the brain and spinal cord, it may prevent toxicity of SOD1 in both familial and sporadic ALS, and may even lead to novel therapeutic approaches for other neurodegenerative diseases involving protein misfolding.

Grants and Awards

“Identifying liver proteins that decrease mutant SOD1 misfolding and decrease SOD1”
NIH-NINDS, R21NS072584-02 (PI, Miller)
The goal of this study is to identify the protein or proteins in the liver that lead to normal handling of SOD1 protein despite the mutations.

Updated January 2019