Role of CD40 ligand in amyloidosis in transgenic Alzheimer's mice

Bibliographic

Year of Publication:

2002

Contact PI Name:

Daniel P. Cardinali

Contact PI Affiliation:

Department of Psychiatry, The Roskamp Institute, University of South Florida, Tampa, Florida, USA.

Co-Authors:

Jun Tan, Terrence Town, Fiona Crawford, Takashi Mori, Anthony DelleDonne, Robert Crescentini, Demian Obregon, Richard A. Flavell

Primary Reference (PubMED ID):

12402041

Funding Source:

Alzheimer's Association

Study Goal and Principal Findings:

We have shown that interaction of CD40 with CD40L enables microglial activation in response to amyloid-beta peptide (Abeta), which is associated with Alzheimer's disease (AD)-like neuronal tau hyperphosphorylation in vivo. Here we report that transgenic mice overproducing Abeta, but deficient in CD40L, showed decreased astrocytosis and microgliosis associated with diminished Abeta levels and beta-amyloid plaque load. Furthermore, in the PSAPP transgenic mouse model of AD, a depleting antibody against CD40L caused marked attenuation of Abeta/beta-amyloid pathology, which was associated with decreased amyloidogenic processing of amyloid precursor protein (APP) and increased circulating levels of Abeta. Conversely, in neuroblastoma cells overexpressing wild-type human APP, the CD40-CD40L interaction resulted in amyloidogenic APP processing. These findings suggest several possible mechanisms underlying mitigation of AD pathology in response to CD40L depletion and validate the CD40-CD40L interaction as a target for therapeutic intervention in AD.

Bibliographic Notes:

Jun Tan and Terrence Town: The first two authors contributed equally to this work

Therapeutic Agent

Therapeutic Information:

Therapy Type:

Biologic - Immunotherapy(passive)

Therapeutic Agent:

anti-CD40L Antibody

PubMed

ClinicalTrials

Patents

Therapeutic Target:

CD40LG

Open Targets

Pharos

Agora

Animal Model

Model Information:

Species:

Mouse

Model Type:

APP

Model Name:

Tg2576

ALZFORUM

Strain/Genetic Background:

C57BL6/SJL

Species:

Mouse

Model Type:

APPxPS1

Model Name:

PS/APP

ALZFORUM

Strain/Genetic Background:

Not Reported

Species:

Mouse

Model Type:

APPxCD40L-Deficient

Model Name:

Tg2576/CD40L-Deficient

PubMed

Strain/Genetic Background:

C57BL6/SJL

Animal Model Notes:

Please view Xu et al., Immunity 1994 Aug;1(5):423-31 (https://pubmed.ncbi.nlm.nih.gov/7882172/) for description of CD40L-deficient mice.

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

Activated Astrocytes

Activated Microglia

Congophillic Amyloid Deposits

Dense-core/Compact Plaques

Biochemical

Amyloid Precursor Protein (APP)

APP-CTF83 (CTF alpha)

APP-CTF99 (CTF beta)

Brain-Buffer Soluble beta Amyloid Peptide 40

Brain-Buffer Soluble beta Amyloid Peptide 42

Brain-Guanidine Soluble beta Amyloid Peptide 40

Brain-Guanidine Soluble beta Amyloid Peptide 42

Immunochemistry

Brain-beta Amyloid Deposits

CD11b

CD45

Glial Fibrillary Acidic Protein (GFAP)

Microscopy

Plaque Characteristics

Cell Biology

Amyloid Precursor Protein (APP)

beta Amyloid Peptides

APP-CTFs