Generating Amyloid Seeds in Lysosomes

2009 Pilot Project Read More

Investigators

Principal Investigator: Carl Frieden, PhD (WashU Biochemistry)
Co-investigators: Marc Diamond, MD (formerly WashU Neurology), Jin-Moo Lee, MD, PhD (WashU Neurology)

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.

Funded Grants

“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

Hope Center Investigators

Carl Frieden

Marc Diamond

Jin-Moo Lee