Alzheimer Disease: Björkdahl C

Pei JJ, Björkdahl C, Zhang H, Zhou X, Winblad B. · Karolinska Institutet, KI-Alzheimer Disease Research Center, Novum, Huddinge, Sweden. · J Alzheimers Dis. · Pubmed #18688088 No free full text.

Abstract: The 70-kDa S6 kinase (p70S6K) is a Ser/Thr (S/T)-directed kinase that plays a crucial role in cell growth, cell differentiation, and cell cycle control. This article presented evidence that supports both toxic and protective roles of p70S6K activity towards tau in Alzheimer's disease (AD) brains. The p70S6K can phosphorylate tau at S262, S214, and T212 sites. Phosphorylation at these sites might release tau from microtubules, resulting in microtubule disruption. Evidence also suggests that p70S6K regulates the translation of tau mRNA by phosphorylating the 40S ribosomal protein S6. The extracellular amyloid-beta deposition in AD brains could be a causative factor that activates p70S6K. We hypothesized that amyloid-beta deposition activates p70S6K whose anti-apoptotic property subsequently keeps neurons from entering into the apoptotic process. This process provides the opportunity for the newly synthesized tau to be phosphorylated by p70S6K and by other tau kinases. This hyperphosphorylated tau then aggregates and is progressively deposited in neurons.

Björkdahl C, Sjögren MJ, Zhou X, Concha H, Avila J, Winblad B, Pei JJ. · Karolinska Institutet, Department of Neurobiology, Care Sciences and Society, KI-Alzheimer's Disease Research Center, Novum, Huddinge, Sweden. · J Neurosci Res. · Pubmed #18061943 No free full text.

Abstract: The heat-shock proteins (HSPs) Hsp27 and alphaB-crystallin are up-regulated in Alzheimer's disease (AD), but the extent of this and the consequences are still largely unknown. The HSPs are involved in protein degradation and protection against protein aggregation, and they interact with several cytoskeletal components such as microtubules (MT) and neurofilaments (NF). AD pathology includes aggregated proteins (tau, NF), decreased protein degradation, and cytoskeletal disruption. It is thus of interest to investigate more closely the possible roles of the HSPs in AD pathology. The expressions of Hsp27 and alphaB-crystallin in AD brain samples were significantly increased (by approximately 20% and approximately 30%, respectively) and correlated significantly with phosphorylated tau and NF proteins. To investigate the consequences of increased HSP levels on tau and NF regulation, N2a cells were transfected with Hsp27 or alphaB-crystallin constructs, and overexpression of the HSPs was confirmed in the cells. Increased tau phosphorylation at the Ser262 site in the N2a cells was regulated by Hsp27 overexpression (possibly through p70S6k), whereas the overexpression of alphaB-crystallin resulted in decreased levels of phosphorylated tau, NF, and GSK-3beta. It was also shown that overexpression of HSPs causes an increase in the percentage of cells present in the G(1) phase. The results presented suggest that a cellular defense against dysregulated proteins, in the form of Hsp27 and alphaB-crystallin, might contribute to the cell cycle reentry seen in AD cells. Furthermore, Hsp27 might also be involved in AD pathology by aggravating MT disruption by tau phosphorylation.

Björkdahl C, Sjögren MJ, Winblad B, Pei JJ. · Division of Experimental Geriatrics, Department of Neurotec, Karolinska Institutet, S-141 86 Huddinge, Sweden. · Neuroreport. · Pubmed #15812314 No free full text.

Abstract: Hyperphosphorylated neurofilaments are a part of neurofibrillary tangles in Alzheimer's disease brains. Zinc has been shown to be increased in the brain areas heavily affected by Alzheimer pathologies. Zinc could induce tau hyperphosphorylation in SH-SY5Y and N2a cells, and tau phosphorylation may be mediated by p70 S6 kinase activation. Many of the tau kinases can also phosphorylate neurofilaments, and in this study we wanted to see whether neurofilament phosphorylation is regulated by p70 S6 kinase in N2a cells. We found that zinc induces rapamycin-dependent p70 S6 kinase phosphorylation at Thr421/Ser424 and Thr389, and rapamycin-independent phosphorylation of neurofilaments at the SMI34 epitope. Although zinc could induce cell proliferation and cell growth, and increased phosphorylation of neurofilaments, only cell growth appeared to be related to p7056kinase activation.