BMP9 ameliorates amyloidosis and the cholinergic defect in a mouse model of Alzheimer's disease.
Bone morphogenetic protein 9 (BMP9) promotes the acquisition of the cholinergic phenotype in basal forebrain cholinergic neurons (BFCN) during development and protects these neurons from cholinergic dedifferentiation following axotomy when administered in vivo. A decline in BFCN function occurs in patients with Alzheimer's disease (AD) and contributes to the AD-associated memory deficits. We infused BMP9 intracerebroventricularly for 7 d in transgenic AD model mice expressing green fluorescent protein specifically in cholinergic neurons (APP.PS1/CHGFP) and in wild-type littermate controls (WT/CHGFP). We used 5-mo-old mice, an age when the AD transgenics display early amyloid deposition and few cholinergic defects, and 10-mo-old mice, by which time these mice exhibit established disease. BMP9 infusion reduced the number of Aβ42-positive amyloid plaques in the hippocampus and cerebral cortex of 5- and 10-mo-old APP.PS1/CHGFP mice and reversed the reductions in choline acetyltransferase protein levels in the hippocampus of 10-mo-old APP.PS1/CHGFP mice. The treatment increased cholinergic fiber density in the hippocampus of both WT/CHGFP and APP.PS1/CHGFP mice at both ages. BMP9 infusion also increased hippocampal levels of neurotrophin 3, insulin-like growth factor 1, and nerve growth factor and of the nerve growth factor receptors, tyrosine kinase receptor A and p75/NGFR, irrespective of the genotype of the mice. These data show that BMP9 administration is effective in reducing the Aβ42 amyloid plaque burden, reversing cholinergic neuron abnormalities, and generating a neurotrophic milieu for BFCN in a mouse model of AD and provide evidence that the BMP9-signaling pathway may constitute a therapeutic target for AD.
Department of Pathology and Laboratory Medicine, Department of Anatomy and Neurobiology, and Department of Pharmacology and Experimental Therapeutics, Boston University School of Medicine, Boston, MA 02118.
Rebecca M
RM
Burke
Timothy A
TA
Norman
Tarik F
TF
Haydar
Barbara E
BE
Slack
Susan E
SE
Leeman
Jan Krzysztof
JK
Blusztajn
Tiffany J
TJ
Mellott
D000544:Alzheimer Disease / Q000378:metabolism*; D000686:Amyloidosis / Q000378:metabolism*; D000704:Analysis of Variance; D000818:Animals; D059329:Cholinergic Neurons / Q000187:drug effects / Q000378:metabolism*; D005260:Female; D055427:Growth Differentiation Factor 2 / Q000008:administration & dosage / Q000378:metabolism / Q000494:pharmacology*; D007118:Immunoassay; D015151:Immunoblotting; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D008856:Microscopy, Fluorescence
C526108:Gdf2 protein, mouse; D055427:Growth Differentiation Factor 2
APPswe PS1dE9 mice; acetylcholine; growth/differentiation factor 2; juvenile protective factors