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.
Highlights
Alzheimer’s disease (AD), the most common form of dementia in the elderly, is characterized by progressive cognitive decline, Aβdeposition, neurofibrillary tangle (NFT) formation, and neurodegeneration[1]
These results fall within the Aβprogression arc originally reported by Cohen and colleagues[38], who detected no amyloid pathology in the cingulate cortex and hippocampus at 6 months of age, yet observed percent area covered with plaques of ~2.5% in the cingulate cortex and ~3% in the hippocampus at 16 months of age
While phosphorylation of tau is a normal process required for regulation of tau binding to microtubules, abnormal phosphorylation, termed hyperphosphorylation, results in paired helical filaments that in turn form NFTs, a pathological hallmark of AD49,50
Summary
Alzheimer’s disease (AD), the most common form of dementia in the elderly, is characterized by progressive cognitive decline, Aβdeposition, neurofibrillary tangle (NFT) formation, and neurodegeneration[1]. A recent study demonstrated the contribution of mural cell degeneration to the progression of AD pathologies: pericyte-deficient platelet-derived growth factor receptor beta (PDGFRβ)knockout mice[11,12] crossed with transgenic mice overexpressing Swedish mutant of human amyloid precursor protein (APPsw) exhibited accelerated progression of Aβaccumulation and cognitive decline[13] In addition to these morphological changes, there is mounting evidence on the significance of cerebrovascular dysfunction for AD progression[14,15,16,17,18]. Examining the neurovascular dysfunction in the presence of both amyloid and tau pathologies is of particular import yet has not been done to date To address this gap, we set out to characterize the extent of early cerebrovascular and neuronal network impairment in the TgF344-AD rat model that exhibits progressive amyloidosis, tauopathy, and frank neuronal loss in addition to cognitive decline[38]. Profound cerebral microvascular and neuronal network dysfunction was demonstrated at the very onset of cognitive dysfunction when soluble Aβspecies and hyperphosphorylated tau begins to rise in this model[38]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
