Genetic ablation of luteinizing hormone receptor improves the amyloid pathology in a mouse model of Alzheimer disease.
Amyloid-beta peptide (Abeta) plays an essential pathophysiologic role in Alzheimer disease, and elevation of luteinizing hormone (LH) levels during aging has been implicated in its pathogenesis. To assess the effect of LH receptor deficiency on Abeta accumulation, we generated a bigenic mouse model, APPsw(+)/Lhr(-/-), which expresses human amyloid precursor protein (APPsw) in the background of LH receptor (Lhr) knockout. Genetic ablation of Lhr resulted in a significant decrease in the number of Abeta plaques and protein content in the hippocampus and cerebral cortex in both male and female mice. Accordingly, several Abeta deposition-related neuropathologic features and functionally relevant molecules were markedly improved, including decreased astrogliosis, reductions of elevated phosphorylated tau, c-fos, alpha7-nicotinic acetylcholine receptor, and restoration of the altered neuropeptide Y receptors Y1 and Y2. Diminution of Abeta accumulation in the absence of LH receptor supports the contention that dysregulation of LH may impact the pathogenesis of Alzheimer disease. The APPsw(+)/Lhr(-/-) mouse may be a useful tool for advancing understanding of the role of LH-mediated events in Alzheimer disease and a model in which to test therapeutic interventions.
Department of Obstetrics, Gynecology and Women's Health, University of Louisville School of Medicine, Louisville, Kentucky 40292, USA.
Jing
J
Lin
Xian
X
Li
Fangping
F
Yuan
Ling
L
Lin
Christine L
CL
Cook
Ch V
ChV
Rao
Zhenmin
Z
Lei
D000544:Alzheimer Disease / Q000235:genetics* / Q000378:metabolism* / Q000503:physiopathology; D016229:Amyloid beta-Peptides / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001921:Brain / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D002540:Cerebral Cortex / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D004195:Disease Models, Animal; D005260:Female; D005911:Gliosis / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D006624:Hippocampus / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D006801:Humans; D007986:Luteinizing Hormone / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D058225:Plaque, Amyloid / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D011974:Receptors, LH / Q000235:genetics*; D017476:Receptors, Neuropeptide Y / Q000378:metabolism; D011978:Receptors, Nicotinic / Q000235:genetics / Q000378:metabolism; D064569:alpha7 Nicotinic Acetylcholine Receptor; D016875:tau Proteins / Q000378:metabolism
D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; C579167:Chrna7 protein, human; C579166:Chrna7 protein, mouse; D016760:Proto-Oncogene Proteins c-fos; D011974:Receptors, LH; D017476:Receptors, Neuropeptide Y; D011978:Receptors, Nicotinic; D064569:alpha7 Nicotinic Acetylcholine Receptor; C095889:neuropeptide Y2 receptor; D016875:tau Proteins; D007986:Luteinizing Hormone