The effect of encapsulated VEGF-secreting cells on brain amyloid load and behavioral impairment in a mouse model of Alzheimer's disease

Bibliographic

Year of Publication:

2010

Contact PI Name:

Eva Carro

Contact PI Affiliation:

Neuroscience Laboratory, Research Center, Madrid, Spain

Co-Authors:

Carlos Spuch, Desiree Antequera, Aitziber Portero, Gorka Orive, Rosa Ma Hernández, Jose A. Molina, Felix Bermejo-Pareja, José L. Pedraz

Primary Reference (PubMED ID):

20430437

Funding Source:

Fondo de Investigacion Sanitaria (FIS)/Fund for the Health of Spain

Spanish Ministry of Science and Innovation

Community of Madrid/Comunidad de Madrid

Study Goal and Principal Findings:

Cerebrovascular dysfunction contributes to cognitive decline and neurodegeneration in Alzheimer's disease (AD). Vascular endothelial growth factor (VEGF), an angiogenic protein with important neurotrophic and neuroprotective actions, is under investigation as a therapeutic agent for the treatment of neurodegenerative disorders. The aim of this study was to generate encapsulated VEGF-secreting cells and implant them in a transgenic mouse model of AD, the double mutant amyloid precursor protein/presenilin 1 (APP/Ps1) mice, which shows a disturbed vessel homeostasis. We report that, after implantation of VEGF microcapsules, brain Abeta burden, hyperphosphorylated-tau and cognitive impairment attenuated in APP/Ps1 mice. Based on the neurovascular hypothesis, this finding suggests a new potential therapeutic approach that could be developed for AD, to enhance Abeta clearance and neurovascular repair, and to protect the cognitive behavior. Stereologically-implanted encapsulated VEGF-secreting cells could offer an alternative strategy in the treatment of AD.

Therapeutic Agent

Therapeutic Information:

Therapy Type:

Biologic - Cell-based

Therapeutic Agent:

VEGF-Secreting Cell Microcapsules

PubMed

ClinicalTrials

Patents

Therapeutic Target:

Vascular Endothelial Growth Factor Receptor (VEGFR)

Open Targets

Pharos

Animal Model

Model Information:

Species:

Mouse

Model Type:

Non-transgenic

Strain/Genetic Background:

C57BL/6

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

Behavioral

T Maze

Novel Object Recognition Test (NORT)

Elevated Plus Maze

Histopathology

Activated Astrocytes

beta Amyloid Deposits

beta Amyloid Load

Dense-core/Compact Plaques

Congophillic Amyloid Deposits

Biochemical

Megalin

Brain-beta Amyloid Peptide-Total

Bcl-2

Caspase 3

Caspase 9

phospho-Mitogen Activated Protein Kinase (phospho-MAPK)

Vascular Endothelial Growth Factor (VEGF)

Glycogen Synthase Kinase 3 beta (GSK3 beta)

phospho-Tau

Akt/phospho-Akt

Receptor for Advanced Glycation Endproducts (RAGE)

Low Density Lipoprotein Receptor-Related Protein 1 (LRP1)

phospho-Glycogen Synthase Kinase 3 beta (phospho-GSK3 beta)

phospho-Extracellular Signal-Regulated Kinase 1/2 (phospho-ERK1/2)

Total Tau Protein

Immunochemistry

Neurogenesis

Glial Fibrillary Acidic Protein (GFAP)

Apoptosis

Angiogenesis

Brain-beta Amyloid Deposits

Activated Astrocytes

Cell Biology

beta Amyloid Peptide Clearance