Amyloid-β Increases Tau by Mediating Sirtuin 3 in Alzheimer’s Disease
Increasing evidence indicates that sirtuin 3 (Sirt3) has neuroprotective effects in regulating oxidative stress and energy metabolism, both of which are involved in the pathogenesis of Alzheimer’s disease (AD). However, it is unclear whether Sirt3 is associated with cognitive performance and pathological changes in AD. We conducted a case-control study of the postmortem brains of AD (n = 16), mild cognitive impairment (n = 13), and age- and education-matched cognitively normal (CN, n = 11) subjects. We measured the mRNA and protein levels of Sirt3 and assessed their association with cognitive performance and AD pathology. In an ex vivo model of cortical neurons from transgenic mice that carry human tau protein, we modified Sirt3 expression by genetic knockdown and knock-in to investigate the cause-effect relationship between Sirt3 and tau. Sirt3 levels were reduced in the entorhinal cortex, the middle temporal gyrus, and the superior frontal gyrus of AD subjects compared to those of CN. This reduction was associated with poorer test scores of neuropsychological evaluation and the severity of tau pathology. Further study with genetic manipulation of Sirt3 revealed that amyloid-β increased levels of total tau acetylated tau through its modulation of Sirt3. These data suggest that reduction of Sirt3 is critically involved in pathogenesis of AD.
KeywordsAlzheimer’s disease Mild cognitive impairment Sirtuin Acetylation Tau Amyloid
The authors are deeply grateful for the subjects and families who have participated in our brain donation program.
Compliance with Ethical Standards
The operations of the Arizona Alzheimer’s Disease Core Center and Banner Sun Health Research Institute Brain and Body Donation Program are approved by their individual Institutional Review Boards. We thus received approval for any experiments using human subjects. Written informed consent was obtained from all subjects (or guardians of subjects) participating in the study [43, 44].
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