title: Transgenic mice overexpressing APP and transforming growth factor-beta1 feature cognitive and vascular hallmarks of Alzheimer's disease.
abstract: High brain levels of amyloid-β (Aβ) and transforming growth factor-β1 (TGF-β1) have been implicated in the cognitive and cerebrovascular alterations of Alzheimer's disease (AD). We sought to investigate the impact of combined increases in Aβ and TGF-β1 on cerebrovascular, neuronal, and mnemonic function using transgenic mice overproducing these peptides (A/T mice). In particular, we measured cerebrovascular reactivity, evoked cerebral blood flow and glucose uptake during brain activation, cholinergic status, and spatial memory, along with cerebrovascular fibrosis, amyloidosis, and astrogliosis, and their evolution with age. An assessment of perfusion and metabolic responses was considered timely, given ongoing efforts for their validation as AD biomarkers. Relative to wild-type littermates, A/T mice displayed an early progressive decline in cerebrovascular dilatory ability, preserved contractility, and reduction in constitutive nitric oxide synthesis that establishes resting vessel tone. Altered levels of vasodilator-synthesizing enzymes and fibrotic proteins, resistance to antioxidant treatment, and unchanged levels of the antioxidant enzyme, superoxide dismutase-2, accompanied these impairments. A/T mice featured deficient neurovascular and neurometabolic coupling to whisker stimulation, cholinergic denervation, cerebral and cerebrovascular Aβ deposition, astrocyte activation, and impaired Morris water maze performance, which gained severity with age. The combined Aβ- and TGF-β1-driven pathology recapitulates salient cerebrovascular, neuronal, and cognitive AD landmarks and yields a versatile model toward highly anticipated diagnostic and therapeutic tools for patients featuring Aβ and TGF-β1 increments.
authors.affiliation: Laboratory of Cerebrovascular Research, Montreal Neurological Institute, McGill University, Montréal, QC, Canada H3A 2B4.
authors.forename: Brice
authors.initials: B
authors.lastname: Ongali
authors.forename: Nektaria
authors.initials: N
authors.lastname: Nicolakakis
authors.forename: Clotilde
authors.initials: C
authors.lastname: Lecrux
authors.forename: Tahar
authors.initials: T
authors.lastname: Aboulkassim
authors.forename: Pedro
authors.initials: P
authors.lastname: Rosa-Neto
authors.forename: Panayiota
authors.initials: P
authors.lastname: Papadopoulos
authors.forename: Xin-Kang
authors.initials: XK
authors.lastname: Tong
authors.forename: Edith
authors.initials: E
authors.lastname: Hamel
mesh_terms: D000544:Alzheimer Disease / Q000235:genetics / Q000473:pathology / Q000503:physiopathology* / Q000523:psychology*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D015415:Biomarkers / Q000032:analysis; D002560:Cerebrovascular Circulation / Q000235:genetics / Q000502:physiology*; D003071:Cognition / Q000502:physiology*; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D008297:Male; D018782:Maze Learning / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D013550:Swimming; D053773:Transforming Growth Factor beta1 / Q000235:genetics* / Q000378:metabolism; D054928:Validation Studies as Topic
chemical_list: D016564:Amyloid beta-Protein Precursor; D015415:Biomarkers; D053773:Transforming Growth Factor beta1