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Long-term treatment of thalidomide ameliorates amyloid-like pathology through inhibition of beta-secretase in a mouse model of Alzheimer’s disease


Year of Publication:
Contact PI Name:
Yong Shen
Contact PI Affiliation:
Center for Advanced Therapeutic Strategies of Brain Disorders, Roskamp Institute, Sarasota, Florida, USA
Ping He, Xin Cheng, Matthias Staufenbiel, Rena Li
Primary Reference (PubMED ID):
Funding Source:
Alzheimer's Association
National Institute on Aging (NIA)
American Health Assistance Foundation
Study Goal and Principal Findings:

Inflammation in the brain has emerged as a significant contributor to the neurodegenerative process in AD.  TNF-alpha is one of the most prominent pro-inflammatory cytokines and plays a central role in initiating and sustaining the cytokine cascade during inflammatory responses. Inhibiting TNF-alpha ameliorates amyloid-associated pathology, prevents the progressive loss of neurons and at last improves cognitive deficits in AD animal models. The authors have previously found that  genetic deletion of TNF receptor I inhibits  Abeta generation through decreasing BACE1 levels and activity, implicating TNFalpha/ TNF receptor I/NF-kB signaling pathway in BACE1 regulation.

In the current study the authors chronically administrated thalidomide on human APPswedish mutation transgenic (APP23) mice from 9 months old (an onset of Abeta deposits and early stage of AD-like changes) to 12 months old.  They found that, in addition of dramatic decrease in the activation of both astrocytes and microglia, thalidomide significantly reduces Abeta load and plaque formation. Furthermore, we found a significant decrease in BACE1 level and activity with long-term thalidomide application. Interestingly, these findings were not observed in the brains of 12-month-old APP23 mice with short-term treatment of thalidomide (3 days). These results suggest that chronic thalidomide administration is an alternative approach for AD prevention and therapeutics. 

Therapeutic Agent

Therapeutic Information:
Therapy Type:
Small Molecule
Therapeutic Agent:
Therapeutic Target:
Multi Target

Animal Model

Model Information:
Model Type:
Strain/Genetic Background:
Model Type:
Strain/Genetic Background:

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 40
Brain-beta Amyloid Peptide 42
beta-Site Amyloid Precursor Protein Cleaving Enzyme 1 (BACE1)
gamma Secretase Components
Insulin Degrading Enzyme (IDE) mRNA
Activated Microglia
Activated Astrocytes