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Regulation of tau phosphorylation in microtubule fractions by apolipoprotein E
1Department of Cell Biology, Emory University School of Medicine, Atlanta, Georgia 30322, USA.
Abstract:
In Alzheimer's disease (AD), a family of proteins collectively named tau are displaced from their normal association with microtubules and are found in in a hyperphosphorylated state deposited into paired helical filaments (PHFs). PHFs are the hallmark cytoskeletal pathology of the disease, and the degree of PHF pathology correlates with the clinical severity of AD. Certain apolipoprotein E (apoE) isoforms have been identified as either risk or protective factors for AD, and one of the proposed mechanisms involves an interaction and potentially modulatory effects on tau hyperphosphorylation by the different apoE isoforms. In these studies, we directly tested the effects of apoE, E2, E3, and E4 on AD-like phosphorylation of tau in brain microtubule fractions. We found that apoE attenuates tau hyperphosphorylation in the fractions, but the pattern was indistinguishable for the different isoforms.
Insights
Apolipoprotein E (apoE) reduces tau hyperphosphorylation in Alzheimer's disease (AD) brain fractions. This effect was consistent across different apoE isoforms (E2, E3, E4), suggesting a general protective mechanism against AD pathology.
Area of Science:
- Neuroscience
- Biochemistry
- Pathology
Background:
- Alzheimer's disease (AD) is characterized by hyperphosphorylated tau protein forming paired helical filaments (PHFs).
- Apolipoprotein E (apoE) isoforms are linked to AD risk, with proposed mechanisms involving modulation of tau pathology.
- The precise interaction between apoE isoforms and tau phosphorylation remains to be fully elucidated.
Purpose of the Study:
- To investigate the direct effects of different apolipoprotein E (apoE) isoforms (E2, E3, E4) on tau hyperphosphorylation.
- To determine if apoE isoforms differentially modulate tau phosphorylation in brain microtubule fractions relevant to Alzheimer's disease.
Main Methods:
- Preparation of brain microtubule fractions.
- Incubation of fractions with recombinant apoE isoforms (E2, E3, E4).
- Assessment of tau phosphorylation levels using biochemical assays.
Main Results:
- Apolipoprotein E (apoE) was found to attenuate tau hyperphosphorylation in brain microtubule fractions.
- The inhibitory effect of apoE on tau hyperphosphorylation was observed across all tested isoforms (E2, E3, and E4).
- No significant differences in the pattern of tau hyperphosphorylation attenuation were found between the different apoE isoforms.
Conclusions:
- Apolipoprotein E (apoE) generally reduces tau hyperphosphorylation, a key pathological event in Alzheimer's disease.
- The protective effect against tau hyperphosphorylation by apoE is not isoform-specific.
- These findings suggest a broad, non-isoform-dependent role for apoE in mitigating tau pathology in AD.