Abstract
BackgroundIn Alzheimer disease (AD), hyperphosphorylation of tau proteins results in microtubule destabilization and cytoskeletal abnormalities. Our prior ultra-morphometric studies documented a clear reduction in microtubules in pyramidal neurons in AD compared to controls, however, this reduction did not coincide with the presence of paired helical filaments. The latter suggests the presence of compensatory mechanism(s) that stabilize microtubule dynamics despite the loss of tau binding and stabilization. Microtubules are composed of tubulin dimers which are subject to posttranslational modifications that affect the stability and function of microtubules.MethodsIn this study, we performed a detailed analysis on changes in the posttranslational modifications in tubulin in postmortem human brain tissues from AD patients and age-matched controls by immunoblot and immunocytochemistry.ResultsConsistent with our previous study, we found decreased levels of α-tubulin in AD brain. Levels of tubulin with various posttranslational modifications such as polyglutamylation, tyrosination, and detyrosination were also proportionally reduced in AD brain, but, interestingly, there was an increase in the proportion of the acetylated α-tubulin in the remaining α-tubulin. Tubulin distribution was changed from predominantly in the processes to be more accumulated in the cell body. The number of processes containing polyglutamylated tubulin was well preserved in AD neurons. While there was a cell autonomous detrimental effect of NFTs on tubulin, this is likely a gradual and slow process, and there was no selective loss of acetylated or polyglutamylated tubulin in NFT-bearing neurons.ConclusionsOverall, we suggest that the specific changes in tubulin modification in AD brain likely represent a compensatory response.
Highlights
In Alzheimer disease (AD), hyperphosphorylation of tau proteins results in microtubule destabilization and cytoskeletal abnormalities
Quantitative analysis, normalized to the levels of glyceraldehyde 3-phosphate dehydrogenase (GAPDH) (Fig. 1b), revealed that levels of total α-tubulin were significantly reduced by approximately 65 % in the brains from AD patients compared to age-matched control brains
Levels of acetylated tubulin, polyglutamylated tubulin, tyrosinated tubulin, and detyrosinated tubulin were significantly reduced in AD brain (Fig. 1b)
Summary
In Alzheimer disease (AD), hyperphosphorylation of tau proteins results in microtubule destabilization and cytoskeletal abnormalities. Our prior ultra-morphometric studies documented a clear reduction in microtubules in pyramidal neurons in AD compared to controls, this reduction did not coincide with the presence of paired helical filaments. The latter suggests the presence of compensatory mechanism(s) that stabilize microtubule dynamics despite the loss of tau binding and stabilization. In AD patients, hyperphosphorylated tau proteins have low tubulin-binding activity and form paired helical filaments which are believed to lead to microtubule destabilization and cytoskeletal abnormalities [3]. Even though the overall function of microtubules and cellular actions dependent on microtubules including axonal transport are likely compromised [5,6,7,8], neurons
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