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Novel therapeutic strategy for neurodegeneration by blocking Aβ seeding mediated aggregation in models of Alzheimer's disease


Year of Publication:
Contact PI Name:
Hilal A. Lashuel
Contact PI Affiliation:
Laboratory of Molecular and Chemical Biology of Neurodegeneration, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland
Simona Eleuteri, Saviana Di Giovanni, Edward Rockenstein, Mike Mante, Antony Adame, Margarita Trejo, Wolf Wrasidlo, Fang Wu, Patrick C. Fraering, Eliezer Masliah
Primary Reference (PubMED ID):
Funding Source:
Swiss Federal Institute of Technology Lausanne
Donald A. Strauss Scholarship Foundation
National Institute on Aging (NIA)
Study Goal and Principal Findings:

This study investigated a library of FDA-approved drugs on Aβ seeding-mediated fibril growth and toxicity. Evidence from genetics, neuropathology, biochemistry and animal models continues to suggest that Aβ aggregation and amyloid formation play central roles in the initiation and progression of neurodegeneration in AD. The nucleated polymerization mechanism is characterized by a nucleation phase associated with the formation of assembly competent oligomers followed by a cooperative oligomer growth and fibril formation by monomer addition. The addition of a small amount of preformed fibrillar aggregates (seeds) eliminates the lag phase of Aβ aggregation and accelerates the fibrillization of monomeric Aβ in vitro and in vivo. Increasing evidence from in vivo studies also suggests that the seeding-mediated aggregation of Aβ proteins is essential for the formation of amyloid plaques, amyloid propagation and spreading via a prion-like mechanism.  Therefore, this study aimed to discover compounds that might interfere with seeding-mediated aggregation and toxicity. Towards this goal, an FDA approved library of bioactive compounds was screened and sixteen molecules were identified as strong inhibitors of Aβ42 seeding-mediated aggregation. Three of these inhibitors, mitoxantrone, bithionol and hexachlorophene,exhibited the strongest inhibition of seeding mediated aggregation and were shown to protect against Aβ-induced neuronal toxicity; these inhibitors were selected for validation in an AD animal model. Herein, these results show that the administration of two of these compounds two months after the initiation of Aβ deposition reduced Aβ accumulation and oligomer formation and protected against Aβ-induced synapse loss and neuronal damage.

Therapeutic Agent

Therapeutic Information:
Therapy Type:
Small Molecule
Therapeutic Agent:
Therapeutic Target:
beta Amyloid Fibril
Therapy Type:
Small Molecule
Therapeutic Agent:
Therapeutic Target:
beta Amyloid Fibril
Therapy Type:
Small Molecule
Therapeutic Agent:
Therapeutic Target:
beta Amyloid Fibril

Animal Model

Model Information:
Model Type:
Strain/Genetic Background:
Model Type:
Strain/Genetic Background:
Not Reported
Animal Model Notes:
Strain/Genetic Background reported in: Rockenstein E, Mallory M, Mante M, Sisk A, Masliah E. Early formation of mature amyloid-β protein deposits in a mutant APP transgenic model depends on levels of Aβ1-42. J Neurosci Res. 2001; 66:573–582. [PubMed: 11746377]; Rockenstein E, Mallory M, Alfrod M, Windisch M, Moessler H, Masliah E. Effects of cerebrolysin on amyloid-beta deposition in a transgenic model of Alzheimer's disease. J Neural Transm Suppl. 2002; 62:327–36. [PubMed: 12456076].

Experimental Design

Is the following information reported in the study?:
Power/Sample Size Calculation
Randomized into Groups
Blinded for Treatment
Blinded for Outcome Measures
Pharmacokinetic Measures
Pharmacodynamic Measures
Toxicology Measures
ADME Measures
Route of Delivery
Duration of Treatment
Frequency of Administration
Age of Animal at the Beginning of Treatment
Age of Animal at the End of Treatment
Sex as a Biological Variable
Study Balanced for Sex as a Biological Variable
Number of Premature Deaths
Number of Excluded Animals
Statistical Plan
Genetic Background
Inclusion/Exclusion Criteria Included
Conflict of Interest


Outcome Measured
Outcome Parameters
beta Amyloid Deposits
Brain-beta Amyloid Peptide 42
gamma Secretase Activity
beta Amyloid Aggregation
beta Amyloid Aggregation
Postsynaptic Density Protein 95 (PSD95)
Microtubule-Associated Protein 2 (MAP2)
Activated Astrocytes
Brain-beta Amyloid Oligomers
Electron Microscopy
Aggregated beta Amyloid Peptide
Dendritic Spines
Synaptic Density
Cell Biology
Neuroprotection-Amyloid Neurotoxicity
Cell Viability
Drug Concentration-Brain
Drug Concentration-Plasma