A cholesterol-lowering drug reduces beta-amyloid pathology in a transgenic mouse model of Alzheimer’s disease

BIBLIOGRAPHIC THERAPEUTIC AGENT ANIMAL MODEL EXPERIMENTAL DESIGN OUTCOMES

Bibliographic

Year of Publication:

2001

Contact PI Name:

Lorenzo M. Refolo

Contact PI Affiliation:

Nathan S. Kline Institute for Psychiatric Research, Orangeburg, New York, USA

Co-Authors:

M.A. Pappolla, J. LaFrancois, B. Malester, S.D. Schmidt, T. Thomas-Bryant, G.S. Tint, R. Wang, M. Mercken, S.S. Petanceska, K.E. Duff

Primary Reference (PubMED ID):

11592856

Funding Source:

Alzheimer's Association

National Institute on Aging (NIA)

Alzheimer's Drug Discovery Foundation (ADDF)

Study Goal and Principal Findings:

The over-arching goal of this study was to determine the effects of a cholesterol-lowering drug BM15.766 on beta-amyloid pathology in the APPPS1 mouse model of Alzheimer's disease. BM15.766 treatment reduced plasma cholesterol, brain Abeta peptides, and beta-amyloid load by greater than twofold. A strong, positive correlation between the amounts of plasma cholesterol and Abeta was observed. Furthermore, drug treatment reduced the amyloidogenic processing of the amyloid precursor protein, suggesting alterations in processing in response to cholesterol modulation. This study demonstrates that hypocholesterolemia is associated with reduced Abeta accumulation suggesting that lowering cholesterol by pharmacological means may be an effective approach for reducing the risk of developing AD.

Therapeutic Agent

Therapeutic Information:

Therapy Type:

Small Molecule

Therapeutic Agent:

BM15.766

PubMed

PubChem

Therapeutic Target:

7-Dehydrocholesterol delta-7 Reductase

Open Targets

Pharos

Agora

Animal Model

Model Information:

Species:

Mouse

Model Type:

APPxPS1

Model Name:

PS/APP

ALZFORUM

Strain/Genetic Background:

Not Reported

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

Biomarkers

Dose

Formulation

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

Outcomes

Outcome Measured

Outcome Parameters

Histopathology

beta Amyloid Load

Biochemical

Brain-beta Amyloid Peptide 40

Brain-beta Amyloid Peptide 42

Amyloid Precursor Protein (APP) Metabolites

Amyloid Precursor Protein (APP)

Brain-Total Cholesterol

Plasma-Total Cholesterol

Pharmacodynamics

Target Engagement (Reduction Total Cholesterol-Plasma)

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