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Sci Rep. 2017 Apr 12;7:46427. doi: 10.1038/srep46427.

Early neurovascular dysfunction in a transgenic rat model of Alzheimer's disease.

Author information

1
Department of Medical Biophysics, University of Toronto, 610 University Avenue, Toronto, Ontario, M5G 2M9, Canada.
2
Sunnybrook Health Sciences Center, 2075 Bayview Avenue, Toronto, Ontario, M4N 3M5, Canada.
3
Fundamental Neurobiology, Krembil Research Institute, University Health Network, 60 Leonard Avenue, Toronto, Ontario, M5T 2R1, Canada.
4
Hospital for Sick Children, 555 University Avenue, Toronto, Ontario, M5G 1X8, Canada.
5
Department of Laboratory Medicine and Pathobiology, University of Toronto, 1 King's College Circle, Toronto, Ontario, M5S 1A1, Canada.

Abstract

Alzheimer's disease (AD), pathologically characterized by amyloid-β peptide (Aβ) accumulation, neurofibrillary tangle formation, and neurodegeneration, is thought to involve early-onset neurovascular abnormalities. Hitherto studies on AD-associated neurovascular injury have used animal models that exhibit only a subset of AD-like pathologies and demonstrated some Aβ-dependent vascular dysfunction and destabilization of neuronal network. The present work focuses on the early stage of disease progression and uses TgF344-AD rats that recapitulate a broader repertoire of AD-like pathologies to investigate the cerebrovascular and neuronal network functioning using in situ two-photon fluorescence microscopy and laminar array recordings of local field potentials, followed by pathological analyses of vascular wall morphology, tau hyperphosphorylation, and amyloid plaques. Concomitant to widespread amyloid deposition and tau hyperphosphorylation, cerebrovascular reactivity was strongly attenuated in cortical penetrating arterioles and venules of TgF344-AD rats in comparison to those in non-transgenic littermates. Blood flow elevation to hypercapnia was abolished in TgF344-AD rats. Concomitantly, the phase-amplitude coupling of the neuronal network was impaired, evidenced by decreased modulation of theta band phase on gamma band amplitude. These results demonstrate significant neurovascular network dysfunction at an early stage of AD-like pathology. Our study identifies early markers of pathology progression and call for development of combinatorial treatment plans.

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