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Shear-Induced Amyloid Formation in the Brain: I. Potential Vascular and Parenchymal Processes.

ABSTRACT: Shear distortion of amyloid-beta (A?) solutions accelerates amyloid cascade reactions that may yield different toxic oligomers than those formed in quiescent solutions. Recent experiments indicate that cerebrospinal fluid (CSF) and interstitial fluid (ISF) containing A? flow through narrow brain perivascular pathways and brain parenchyma. This paper suggests that such flow causes shear distortion of A? molecules involving conformation changes that may be one of the initiating events in the etiology of Alzheimer's disease. A? shearing can occur in or around brain arteries and arterioles and is suggested as the origin of cerebral amyloid angiopathy deposits in cerebrovascular walls. Comparatively low flow rates of ISF within the narrow extracellular spaces (ECS) of the brain parenchyma are suggested as a possible initiating factor in both the formation of neurotoxic A?42 oligomers and amyloid fibrils. A?42 in slow-flowing ISF can gain significant shear energy at or near the walls of tortuous brain ECS flow paths, promoting the formation of a shear-distorted, excited state hydrophobic A?42* conformation. This A?42* molecule could possibly be involved in one of two paths, one involving rapid adsorption to a brain membrane surface, ultimately forming neurotoxic oligomers on membranes, and the other ultimately forming plaque within the ECS flow pathways. Rising A? concentrations combined with shear at or near critical brain membranes are proposed as contributing factors to Alzheimer's disease neurotoxicity. These hypotheses may be applicable in other neurodegenerative diseases, including tauopathies and alpha-synucleinopathies, in which shear-distorted proteins also may form in the brain ECS.

SUBMITTER: Trumbore CN

PROVIDER: S-EPMC5026135 | biostudies-literature | 2016 Sep

REPOSITORIES: biostudies-literature

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Shear-Induced Amyloid Formation in the Brain: I. Potential Vascular and Parenchymal Processes.

Trumbore Conrad N CN

Journal of Alzheimer's disease : JAD 20160901 2

Shear distortion of amyloid-beta (Aβ) solutions accelerates amyloid cascade reactions that may yield different toxic oligomers than those formed in quiescent solutions. Recent experiments indicate that cerebrospinal fluid (CSF) and interstitial fluid (ISF) containing Aβ flow through narrow brain perivascular pathways and brain parenchyma. This paper suggests that such flow causes shear distortion of Aβ molecules involving conformation changes that may be one of the initiating events in the etiol ...[more]

PMID: 27567812

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Project description:BackgroundAccumulation and deposition of ?-amyloid peptides (A?) in the brain is a central event in the pathogenesis of Alzheimer's disease (AD). Besides the parenchymal pathology, A? is known to undergo active transport across the blood-brain barrier and cerebral amyloid angiopathy (CAA) is a prominent feature in the majority of AD. Although impaired cerebral blood flow (CBF) has been implicated in faulty A? transport and clearance, and cerebral hypoperfusion can exist in the pre-clinical phase of Alzheimer's disease (AD), it is still unclear whether it is one of the causal factors for AD pathogenesis, or an early consequence of a multi-factor condition that would lead to AD at late stage. To study the potential interaction between faulty CBF and amyloid accumulation in clinical-relevant situation, we generated a new amyloid precursor protein (APP) knock-in allele that expresses humanized A? and a Dutch mutation in addition to Swedish/London mutations and compared this line with an equivalent knock-in line but in the absence of the Dutch mutation, both crossed onto the PS1M146V knock-in background.ResultsIntroduction of the Dutch mutation results in robust CAA and parenchymal A? pathology, age-dependent reduction of spatial learning and memory deficits, and CBF reduction as detected by fMRI. Direct manipulation of CBF by transverse aortic constriction surgery on the left common carotid artery caused differential changes in CBF in the anterior and middle region of the cortex, where it is reduced on the left side and increased on the right side. However these perturbations in CBF resulted in the same effect: both significantly exacerbate CAA and amyloid pathology.ConclusionsOur study reveals a direct and positive link between vascular and parenchymal A?; both can be modulated by CBF. The new APP knock-in mouse model recapitulates many symptoms of AD including progressive vascular and parenchymal A? pathology and behavioral deficits in the absence of APP overexpression.

Dataset Information

Shear-Induced Amyloid Formation in the Brain: I. Potential Vascular and Parenchymal Processes.

Publications

Shear-Induced Amyloid Formation in the Brain: I. Potential Vascular and Parenchymal Processes.

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