Dataset Information

An Aged Canid with Behavioral Deficits Exhibits Blood and Cerebrospinal Fluid Amyloid Beta Oligomers.

ABSTRACT: Many of the molecular and pathological features associated with human Alzheimer disease (AD) are mirrored in the naturally occurring age-associated neuropathology in the canine species. In aged dogs with declining learned behavior and memory the severity of cognitive dysfunction parallels the progressive build up and location of A? in the brain. The main aim of this work was to study the biological behavior of soluble oligomers isolated from an aged dog with cognitive dysfunction through investigating their interaction with a human cell line and synthetic A? peptides. We report that soluble oligomers were specifically detected in the dog's blood and cerebrospinal fluid (CSF) via anti-oligomer- and anti-A? specific binders. Importantly, our results reveal the potent neurotoxic effects of the dog's CSF on cell viability and the seeding efficiency of the CSF-borne soluble oligomers on the thermodynamic activity and the aggregation kinetics of synthetic human A?. The value of further characterizing the naturally occurring Alzheimer-like neuropathology in dogs using genetic and molecular tools is discussed.

SUBMITTER: Rusbridge C

PROVIDER: S-EPMC5797595 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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An Aged Canid with Behavioral Deficits Exhibits Blood and Cerebrospinal Fluid Amyloid Beta Oligomers.

Rusbridge Clare C Salguero Francisco J FJ David Monique Antoinette MA Faller Kiterie M E KME Bras Jose T JT Guerreiro Rita J RJ Richard-Londt Angela C AC Grainger Duncan D Head Elizabeth E Brandner Sebastian G P SGP Summers Brian B Hardy John J Tayebi Mourad M

Frontiers in aging neuroscience 20180130

Many of the molecular and pathological features associated with human Alzheimer disease (AD) are mirrored in the naturally occurring age-associated neuropathology in the canine species. In aged dogs with declining learned behavior and memory the severity of cognitive dysfunction parallels the progressive build up and location of Aβ in the brain. The main aim of this work was to study the biological behavior of soluble oligomers isolated from an aged dog with cognitive dysfunction through investi ...[more]

PMID: 29441010

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Project description:To improve the ability to develop treatments that prevent incipient Alzheimer disease (AD) from progressing to overt AD, it is important to understand the molecular basis of the earliest pathophysiological abnormalities and to determine how amyloid-? (A?) is involved very early in its pathogenesis.To investigate 2 specific A? oligomers, A? trimers and A?*56, in human cerebrospinal fluid (CSF); evaluate the effects of aging and AD; and obtain support for the hypothesis that they may be pathogenic by determining their relationships to CSF tau.A CSF sampling study.The University of Minnesota Medical School in Minneapolis, Minnesota, and the Salhgrenska University Hospital, Sweden.Forty-eight older adults with mild cognitive impairment or AD (impaired group); 49 age-matched cognitively intact control subjects (unimpaired group); and 10 younger, normal control subjects.Measurements of CSF A? trimers, A?*56, the 42-amino acid A? isoform (A?1-42), total tau (T-tau), and phospho-tau 181 (p-tau(181)). The hypothesis being tested was formulated after data collection. RESULTS We observed that A? trimers and A?*56 levels increased with age; within the unimpaired group, they were elevated in subjects with T-tau/A?1-42 ratios greater than a cutoff that distinguished the unimpaired group from subjects with AD. In the unimpaired group, T-tau and p-tau(181) were found to correlate strongly with A? trimers and A?*56 (r > 0.63), but not with A?1-42 (-0.10 < r < -0.01). The strong correlations were found to be attenuated in the impaired group.In cognitively intact older adults, CSF A? trimers and A?*56 were elevated in individuals at risk for AD, and they showed stronger relationships with tau than did A?1-42, a surrogate for A? fibril deposition. These findings suggest that prior to overt symptoms, 1 or both of the A? oligomers, but not fibrillar A?, is coupled to tau; however, this coupling is weakened or broken when AD advances to symptomatic stages. The uncoupling is interesting in light of the failure of experimental A? therapies to improve mild cognitive impairment/AD, which has prompted a shift in the timing of A? therapies to asymptomatic subjects. Knowing which A? species to target in asymptomatic subjects may enhance the success of future treatments for AD.

Dataset Information

An Aged Canid with Behavioral Deficits Exhibits Blood and Cerebrospinal Fluid Amyloid Beta Oligomers.

Publications

An Aged Canid with Behavioral Deficits Exhibits Blood and Cerebrospinal Fluid Amyloid Beta Oligomers.

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