title: High levels of homocysteine results in cerebral amyloid angiopathy in mice.
abstract: High levels of homocysteine is a risk factor for developing Alzheimer's disease (AD), and the effect that this amino acid has on amyloid-β (Aβ) protein precursor metabolism is considered one of the potential mechanism(s) involved in this effect. However, despite consistent literature indicating that this condition results in brain parenchyma amyloidosis, no data are available on whether it may also influence the amount of Aβ deposited in the vasculature. To test this hypothesis, we implemented a model of diet-inducing high homocysteinemia in AD transgenic mice, 3xTg, and assessed them for the development of cerebral amyloid angiopathy (CAA). Compared with controls, mice with high homocysteine showed a significant increase in the amount of Aβ deposited in the brain vasculature, which was not associated with histological evidence of microhemorrhage occurrence. Mice with high homocysteine had a significant reduction in steady state level of the apolipoprotein E, which is a main Aβ chaperon protein, but no changes in its receptor, the low-density-lipoprotein-receptor-1. Our data demonstrate that a diet-induced high homocysteine level favors the development of CAA via a reduction of Aβ clearance and transport within the brain. Therapeutic approaches aimed at restoring brain apolipoprotein E levels should be considered in individuals carrying this environmental risk factor in order to reduce the incidence of homocysteine-dependent CAA.
authors: Department of Pharmacology and Center for Translational Medicine, Temple University School of Medicine, Philadelphia, PA, USA.
authors: Jian-Guo
authors: JG
authors: Li
authors: Department of Pharmacology and Center for Translational Medicine, Temple University School of Medicine, Philadelphia, PA, USA.
authors: Domenico
authors: D
authors: Praticò
mesh_terms: D000544:Alzheimer Disease; D016229:Amyloid beta-Peptides / Q000378:metabolism; D000821:Animal Feed; D000818:Animals; D001921:Brain / Q000098:blood supply / Q000378:metabolism / Q000473:pathology; D016657:Cerebral Amyloid Angiopathy / Q000209:etiology* / Q000473:pathology / Q000503:physiopathology*; D004032:Diet; D004195:Disease Models, Animal; D005260:Female; D006710:Homocysteine / Q000008:administration & dosage / Q000378:metabolism; D020138:Hyperhomocysteinemia / Q000150:complications* / Q000473:pathology / Q000503:physiopathology*; D008297:Male; D008822:Mice, Transgenic; D011897:Random Allocation
chemical_list: D016229:Amyloid beta-Peptides; D006710:Homocysteine
keywords: Alzheimer's disease; amyloid-β; homocysteine; transgenic mouse model