The autophagy-related protein beclin 1 shows reduced expression in early Alzheimer disease and regulates amyloid beta accumulation in mice.
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.
Pickford
Fiona
F
Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, California, USA.
Masliah
Eliezer
E
Britschgi
Markus
M
Lucin
Kurt
K
Narasimhan
Ramya
R
Jaeger
Philipp A
PA
Small
Scott
S
Spencer
Brian
B
Rockenstein
Edward
E
Levine
Beth
B
Wyss-Coray
Tony
T
D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000737:chemistry / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism*; D000818:Animals; D051017:Apoptosis Regulatory Proteins; D001343:Autophagy; D000071186:Beclin-1; D001921:Brain / Q000378:metabolism*; D002462:Cell Membrane / Q000378:metabolism; D011992:Endosomes / Q000378:metabolism; D031541:Fluorescence Resonance Energy Transfer; D005786:Gene Expression Regulation; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D009474:Neurons / Q000378:metabolism*; D011506:Proteins / Q000378:metabolism*
D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D051017:Apoptosis Regulatory Proteins; D000071186:Beclin-1; C115010:Becn1 protein, mouse; D011506:Proteins