Small heat shock proteins Hsp27 or αB‐crystallin and the protein components of neurofibrillary tangles: Tau and neurofilaments

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.

The small heat shock protein Hsp27 protects cortical neurons against the toxic effects of β‐amyloid peptide

“…In this latter report, Hsp27 also facilitated the degradation of the hyperphosphorylated tau in an unbiquitin-independent manner (which distinguishes its effect from the ubiquitin-dependent effects of the Hsp70/ CHIP chaperone complex on tau (Carrettiero et al, 2009). However, it has also been suggested that the binding of Hsp27 to tau might actually promote the disease process in AD by aggravating disruption of microtubules by hyperphosphorylated tau (Bjorkdahl et al, 2008).…”

Mammalian Target of Rapamycin (mTor) Mediates Tau Protein Dyshomeostasis

“…Previously we have extensively studied the role of mTor signaling and tau hyperphosphorylation in SH-SY5Y cells, murine N2a neuroblastoma cells, rat primary neurons, and metabolically active rat brain slices that were treated with a physiological or pathological dosage of zinc (21,31,44,51,56,57). In the present study, the role of mTor in biochemical changes (translation, phosphorylation, and aggregation) of tau was studied in AD brains, by in vitro phosphorylation plus mass spectrometry, and in SH-SY5Y cells with different genetic modifications of mTor activity.…”

HspB5/αB-Crystallin in the Brain

“…In contrast, neurofi brillary tangles are formed by hyperphosphorylation of the microtubule associated protein tau and neurofi laments. HspB5 is upregulated in AD brains and localized in all type of glia cells in the areas rich in senile plaques (Bjorkdahl et al 2008 ;Renkawek et al 1994 ;Wilhelmus et al 2006b ). It was also found in neurons in the limbic system of AD brains especially in late stages of AD and areas rich in neurofi brillary tangles (Mao et al 2001 ).…”