Title
Specific amyloid-beta oligomers in-human cerebrospinal fluid.
Abstract
Alzheimer’s disease (AD) is a progressive neurodegenerative disease with a long
preclinical stage, during which pathological changes and biomarker abnormalities, such
as elevations of tau proteins in the cerebrospinal fluid (CSF), occur in the absence of
cognitive impairment. Research on the etiology of AD in cell culture and animals have
suggested that soluble oligomers of amyloid-β (Aβ), such as Aβ*56, trimers, and dimers,
are the synaptotoxic species in AD and are thought to be responsible for initiating the
cognitive impairment associated with the early stages of disease. These studies also
suggest that tau pathology develops downstream of Aβ and may mediate the detrimental
effects of Aβ on learning and memory. However, the whether these Aβ oligomers exist in
humans and are associated with disease processes of AD is still unknown. To address this
question, we developed a sensitive method to detect Aβ*56, trimers, and dimers in
lumbar CSF, enabling the study of these oligomers in clinically characterized living
subjects. Biochemical study of CSF from cognitively intact subjects and impaired
subjects with clinical diagnosis of AD and mild cognitive impairment (MCI) showed that
these oligomers were present in the CSF of both the unimpaired and impaired subjects.Within the unimpaired group, subjects at a higher risk of having preclinical AD had
elevated levels of Aβ oligomers. Furthermore, Aβ*56, dimers, and trimers were
positively correlated with total or abnormally phosphorylated tau in the CSF of
unimpaired subjects, suggesting that these oligomers are associated with disease
processes and may induce tau abnormalities in the preclinical phase of disease. Study of
CSF from subjects enrolled in a longitudinal study showed that Aβ*56 was negatively
correlated with memory in unimpaired subjects who converted to MCI/AD during
follow-up. However, baseline Aβ oligomer levels were not predictive of conversion to
MCI/AD from cognitive normality. Further exploratory analysis revealed significant
associations between high levels of baseline total tau or low Aβ*56 levels and a faster
rate of memory decline. The results of these studies are consistent with the hypothesis
that Aβ oligomers may trigger tau abnormalities in preclinical AD, and that Aβ*56 may
play a pathological role in preclinical AD but is not sufficient to trigger disease progression. A hypothetical model describing the characteristics of Aβ*56 and tau during
the preclinical phase of AD was generated from this data and awaits further evaluation.
Description
University of Minnesota Ph.D. dissertation. August 2012. Major: Neuroscience. Advisor:Karen H. Ashe M.D., Ph.D. 1 computer file (PDF); viii, 213 pages.
Suggested Citation
Handoko, Maureen.
(2012).
Specific amyloid-beta oligomers in-human cerebrospinal fluid..
Retrieved from the University of Minnesota Digital Conservancy,
https://hdl.handle.net/11299/137025.