Increased BMP6 levels in the brains of Alzheimer's disease patients and APP transgenic mice are accompanied by impaired neurogenesis.
During aging and in the progression of Alzheimer's disease (AD), synaptic plasticity and neuronal integrity are disturbed. In addition to the alterations in plasticity in mature neurons, the neurodegenerative process in AD has been shown to be accompanied by alterations in neurogenesis. Members of the bone morphogenetic protein (BMP) family of growth factors have been implicated as important regulators of neurogenesis and neuronal cell fate determination during development; however, their role in adult neurogenesis and in AD is less clear. We show here by qRT-PCR analysis that BMP6 mRNA levels were significantly increased in the hippocampus of human patients with AD and in APP transgenic mice compared to controls. Immunoblot and immunohistochemical analyses confirmed that BMP6 protein levels were increased in human AD brains and APP transgenic mouse brains compared to controls and accumulated around hippocampal plaques. The increased levels of BMP6 were accompanied by defects in hippocampal neurogenesis in AD patients and APP transgenic mice. In support of a role for BMP6 in defective neurogenesis in AD, we show in an in vitro model of adult neurogenesis that treatment with amyloid-β(1-42) protein (Aβ) resulted in increased expression of BMP6, and that exposure to recombinant BMP6 resulted in reduced proliferation with no toxic effects. Together, these results suggest that Aβ-associated increases in BMP6 expression in AD may have deleterious effects on neurogenesis in the hippocampus, and therapeutic approaches could focus on normalization of BMP6 levels to protect against AD-related neurogenic deficits.
Crews
Leslie
L
Departments of Neurosciences and Pathology, University of California, San Diego, La Jolla, California 92093-0624.
Adame
Anthony
A
Patrick
Christina
C
Delaney
Alexandra
A
Pham
Emiley
E
Rockenstein
Edward
E
Hansen
Lawrence
L
Masliah
Eliezer
E
D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D016564:Amyloid beta-Protein Precursor / Q000235:genetics* / Q000502:physiology; D000818:Animals; D055418:Bone Morphogenetic Protein 6 / Q000096:biosynthesis* / Q000235:genetics* / Q000502:physiology; D001923:Brain Chemistry / Q000235:genetics; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D009433:Neural Inhibition / Q000235:genetics*; D055495:Neurogenesis / Q000235:genetics; D015854:Up-Regulation / Q000235:genetics*
D016564:Amyloid beta-Protein Precursor; C525816:BMP6 protein, human; D055418:Bone Morphogenetic Protein 6