14-3-3 proteins and zeta isoform containing neurofibrillary tangles in patients with Alzheimer?s disease

Abstract

Immunolocalization of 14-3-3 proteins in Alzheimer's disease (AD) brains was investigated using isoform-specific antibodies. Weak granular immunoreactivity of 14-3-3 proteins was found in neuronal cytoplasm in control subjects and AD brains. Both intracellular and extracellular neurofibrillary tangles (NFTs), as well as neuropil thread-like structures, were immunopositive for 14-3-3 proteins. This was corroborated by triple-fluorolabeling method visualizing paired helical filament (PHF) tau and 14-3-3 epitopes in relation to fibrillary state detected by thiazin red. Pretangle neurons (positive for PHF-tau without fibrillary structure detected by thiazin red) only contained fine granular immunoreactivity (IR) of 14-3-3, which was similarly found in unaffected neurons. Granular cytoplasmic IR of 14-3-3 proteins in pretangle neurons was not colocalized to granular tau-like IR, which suggests that participation of 14-3-3 proteins in NFT formation was restricted to its later stages. Its zeta isoform was most prominent in these NFTs, suggesting that this isoform is a major component involved in the formation of NFTs. In contrast, IR of epsilon isoform was found in the neuropil of the hippocampus and that of sigma isoform was localized to granule cells of the dentate gyrus in AD brains, as seen in the age-matched controls. Expression of 14-3-3 proteins were found to be highly variable and dependent on their isoforms, regions and cell types. Molecular, as well as topographical, dissection of 14-3-3 proteins will provide us with an improved understanding of this molecule in normal and pathological conditions.

Deleting the 14-3-3 Protein Bmh1 Extends Life Span inSaccharomyces cerevisiaeby Increasing Stress Response

“…However, it remains unclear how and which types of 14-3-3 protein abnormalities contribute to the cause of these diseases. 14-3-3 protein levels are abundant in the neurofibrillary tangle in patients with Alzheimer's disease (Umahara et al 2004). Elevated 14-3-3 expressions in lung and breast cancers have also been described.…”

Dysregulation of 14‐3‐3 proteins in neurodegenerative diseases with Lewy body or Alzheimer pathology

“…14‐3‐3s also interact with proteins implicated in other neurodegenerative disorders, including beta‐amyloid (A β ), tau, superoxide dismutase, and huntingtin 18, 19, 20, 21, 22. 14‐3‐3s colocalize with these aggregation‐prone proteins in neurofibrillary tangles and plaques of Alzheimer's disease (AD), Huntington's disease (HD) inclusion bodies, and inclusions observed in amyotrophic lateral sclerosis (ALS) 20, 23, 24, 25…”

14-3-3 targets chaperone-associated misfolded proteins to aggresomes

“…In addition, 14-3-3 proteins have been implicated in a number of neurodegenerative disorders, largely based on the observation that 14-3-3 proteins co-localize with the pathological inclusion bodies associated with these diseases, including Lewy bodies in Parkinson's disease, neurofibrillary tangles in Alzheimer's disease, mutant huntingtin aggregates in Huntington's disease, etc. (Chen et al, 2003;Kawamoto et al, 2002;Umahara et al, 2004). However, it is not known how and why 14-3-3 assembles in these inclusion bodies (Foote and Zhou, 2012).…”