The autophagy-related protein beclin 1 shows reduced expression in early Alzheimer disease and regulates amyloid beta accumulation in mice.

Abstract

Autophagy is the principal cellular pathway for degradation of long-lived proteins and organelles and regulates cell fate in response to stress. Recently, autophagy has been implicated in neurodegeneration, but whether it is detrimental or protective remains unclear. Here we report that beclin 1, a protein with a key role in autophagy, was decreased in affected brain regions of patients with Alzheimer disease (AD) early in the disease process. Heterozygous deletion of beclin 1 (Becn1) in mice decreased neuronal autophagy and resulted in neurodegeneration and disruption of lysosomes. In transgenic mice that express human amyloid precursor protein (APP), a model for AD, genetic reduction of Becn1 expression increased intraneuronal amyloid beta (Abeta) accumulation, extracellular Abeta deposition, and neurodegeneration and caused microglial changes and profound neuronal ultrastructural abnormalities. Administration of a lentiviral vector expressing beclin 1 reduced both intracellular and extracellular amyloid pathology in APP transgenic mice. We conclude that beclin 1 deficiency disrupts neuronal autophagy, modulates APP metabolism, and promotes neurodegeneration in mice and that increasing beclin 1 levels may have therapeutic potential in AD.

• Authors: Fiona Pickford, Eliezer Masliah, Markus Britschgi, Kurt Lucin, Ramya Narasimhan, Philipp A Jaeger, Scott Small, Brian Spencer, Edward Rockenstein, Beth Levine, Tony Wyss-Coray
• Journal: The Journal of clinical investigation (J Clin Invest) Vol. 118 Issue 6 Pg. 2190-9 (Jun 2008) ISSN: 0021-9738 [Print] United States
• PMID: 18497889 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Amyloid beta-Peptides
• Amyloid beta-Protein Precursor
• Apoptosis Regulatory Proteins
• Beclin-1
• Becn1 protein, mouse
• Proteins

Topics

• Alzheimer Disease (genetics, metabolism)
• Amyloid beta-Peptides (chemistry, metabolism)
• Amyloid beta-Protein Precursor (metabolism)
• Animals
• Apoptosis Regulatory Proteins
• Autophagy
• Beclin-1
• Brain (metabolism)
• Cell Membrane (metabolism)
• Endosomes (metabolism)
• Fluorescence Resonance Energy Transfer
• Gene Expression Regulation
• Humans
• Mice
• Mice, Transgenic
• Neurons (metabolism)
• Proteins (metabolism)