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Chaperone signalling complexes in Alzheimer's disease.

Koren J, Jinwal UK, Lee DC, Jones JR, Shults CL, Johnson AG, Anderson LJ, Dickey CA - J. Cell. Mol. Med. (2009)

Bottom Line: To the best of our current knowledge, the chaperone system in eukaryotic cells revolves around the ATPase activities of Hsp70 and Hsp90, the two primary chaperone scaffolds.Other chaperones and co-chaperones manipulate the ATPase activities of Hsp70 and Hsp90, facilitating either folding of the client or its degradation.Here, we present the current understandings of chaperone biology and examine the literature investigating these proteins in the context of AD.

View Article: PubMed Central - PubMed

Affiliation: Johnnie B. Byrd Sr. Alzheimer's Center and Research Institute, Department of Molecular Medicine, University of South Florida, Tampa, USA.

ABSTRACT
Molecular chaperones and heat shock proteins (Hsp) have emerged as critical regulators of proteins associated with neurodegenerative disease pathologies. The very nature of the chaperone system, which is to maintain protein quality control, means that most nascent proteins come in contact with chaperone proteins. Thus, amyloid precursor protein (APP), members of the gamma-secretase complex (presenilin 1 [PS1] collectively), the microtubule-associated protein tau (MAPT) as well as a number of neuroinflammatory components are all in contact with chaperones from the moment of their production. Chaperones are often grouped together as one machine presenting abnormal or mutant proteins to the proteasome for degradation, but this is not at all the case. In fact, the chaperone family consists of more than 100 proteins in mammalian cells, and the primary role for most of these proteins is to protect clients following synthesis and during stress; only as a last resort do they facilitate protein degradation. To the best of our current knowledge, the chaperone system in eukaryotic cells revolves around the ATPase activities of Hsp70 and Hsp90, the two primary chaperone scaffolds. Other chaperones and co-chaperones manipulate the ATPase activities of Hsp70 and Hsp90, facilitating either folding of the client or its degradation. In the case of Alzheimer's disease (AD), a number of studies have recently emerged describing the impact that these chaperones have on the proteotoxic effects of tau and amyloid- beta accumulation. Here, we present the current understandings of chaperone biology and examine the literature investigating these proteins in the context of AD.

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Heat shock proteins and chaperones are elevated in Alzheimer's brain. (A) Brain tissue from medial temporal gyrus of two Alzheimer's disease (AD) patients and two age/gender-matched controls were homogenised and analysed by Western blot. Chaperone proteins were dramatically elevated in AD brain compared with control. ptau antibody recognising tau phosphorylated at pS212 was used to confirm pathology. GAPDH levels were unchanged. (B) Brain sections from rTg4510 transgenic mice that have inducible P301L human tau expression in the forebrain and non-transgenic littermates were stained with an anti-Hsp27 antibody. Dramatic gliosis was evident throughout the CA1 and caudate putamen and along the alveus in transgenic mice compared with control.
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fig01: Heat shock proteins and chaperones are elevated in Alzheimer's brain. (A) Brain tissue from medial temporal gyrus of two Alzheimer's disease (AD) patients and two age/gender-matched controls were homogenised and analysed by Western blot. Chaperone proteins were dramatically elevated in AD brain compared with control. ptau antibody recognising tau phosphorylated at pS212 was used to confirm pathology. GAPDH levels were unchanged. (B) Brain sections from rTg4510 transgenic mice that have inducible P301L human tau expression in the forebrain and non-transgenic littermates were stained with an anti-Hsp27 antibody. Dramatic gliosis was evident throughout the CA1 and caudate putamen and along the alveus in transgenic mice compared with control.

Mentions: Involvement of chaperones in the pathogenesis of AD was first proposed following promoter analysis of the APP gene, where an HSE was found within its promoter [89]. Immunohistochemical studies and expression analyses in AD brain tissue showed that expression levels of a number of Hsps, particularly Hsp27 and Hsp70, were elevated in affected regions from AD brain tissue, and this elevation appears to be a hybridisation of activated glia and dysregulated/stressed neurons (Fig. 1A and B) [90–96]. Since then, pathological structures typical of AD have been shown to harbour other chaperone proteins, such as CHIP [97] and Parkin [98]. These findings have served as the foundation for a number of mechanistic studies regarding the impact of chaperones and stress on the contributors to AD pathogenesis.


Chaperone signalling complexes in Alzheimer's disease.

Koren J, Jinwal UK, Lee DC, Jones JR, Shults CL, Johnson AG, Anderson LJ, Dickey CA - J. Cell. Mol. Med. (2009)

Heat shock proteins and chaperones are elevated in Alzheimer's brain. (A) Brain tissue from medial temporal gyrus of two Alzheimer's disease (AD) patients and two age/gender-matched controls were homogenised and analysed by Western blot. Chaperone proteins were dramatically elevated in AD brain compared with control. ptau antibody recognising tau phosphorylated at pS212 was used to confirm pathology. GAPDH levels were unchanged. (B) Brain sections from rTg4510 transgenic mice that have inducible P301L human tau expression in the forebrain and non-transgenic littermates were stained with an anti-Hsp27 antibody. Dramatic gliosis was evident throughout the CA1 and caudate putamen and along the alveus in transgenic mice compared with control.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2749087&req=5

fig01: Heat shock proteins and chaperones are elevated in Alzheimer's brain. (A) Brain tissue from medial temporal gyrus of two Alzheimer's disease (AD) patients and two age/gender-matched controls were homogenised and analysed by Western blot. Chaperone proteins were dramatically elevated in AD brain compared with control. ptau antibody recognising tau phosphorylated at pS212 was used to confirm pathology. GAPDH levels were unchanged. (B) Brain sections from rTg4510 transgenic mice that have inducible P301L human tau expression in the forebrain and non-transgenic littermates were stained with an anti-Hsp27 antibody. Dramatic gliosis was evident throughout the CA1 and caudate putamen and along the alveus in transgenic mice compared with control.
Mentions: Involvement of chaperones in the pathogenesis of AD was first proposed following promoter analysis of the APP gene, where an HSE was found within its promoter [89]. Immunohistochemical studies and expression analyses in AD brain tissue showed that expression levels of a number of Hsps, particularly Hsp27 and Hsp70, were elevated in affected regions from AD brain tissue, and this elevation appears to be a hybridisation of activated glia and dysregulated/stressed neurons (Fig. 1A and B) [90–96]. Since then, pathological structures typical of AD have been shown to harbour other chaperone proteins, such as CHIP [97] and Parkin [98]. These findings have served as the foundation for a number of mechanistic studies regarding the impact of chaperones and stress on the contributors to AD pathogenesis.

Bottom Line: To the best of our current knowledge, the chaperone system in eukaryotic cells revolves around the ATPase activities of Hsp70 and Hsp90, the two primary chaperone scaffolds.Other chaperones and co-chaperones manipulate the ATPase activities of Hsp70 and Hsp90, facilitating either folding of the client or its degradation.Here, we present the current understandings of chaperone biology and examine the literature investigating these proteins in the context of AD.

View Article: PubMed Central - PubMed

Affiliation: Johnnie B. Byrd Sr. Alzheimer's Center and Research Institute, Department of Molecular Medicine, University of South Florida, Tampa, USA.

ABSTRACT
Molecular chaperones and heat shock proteins (Hsp) have emerged as critical regulators of proteins associated with neurodegenerative disease pathologies. The very nature of the chaperone system, which is to maintain protein quality control, means that most nascent proteins come in contact with chaperone proteins. Thus, amyloid precursor protein (APP), members of the gamma-secretase complex (presenilin 1 [PS1] collectively), the microtubule-associated protein tau (MAPT) as well as a number of neuroinflammatory components are all in contact with chaperones from the moment of their production. Chaperones are often grouped together as one machine presenting abnormal or mutant proteins to the proteasome for degradation, but this is not at all the case. In fact, the chaperone family consists of more than 100 proteins in mammalian cells, and the primary role for most of these proteins is to protect clients following synthesis and during stress; only as a last resort do they facilitate protein degradation. To the best of our current knowledge, the chaperone system in eukaryotic cells revolves around the ATPase activities of Hsp70 and Hsp90, the two primary chaperone scaffolds. Other chaperones and co-chaperones manipulate the ATPase activities of Hsp70 and Hsp90, facilitating either folding of the client or its degradation. In the case of Alzheimer's disease (AD), a number of studies have recently emerged describing the impact that these chaperones have on the proteotoxic effects of tau and amyloid- beta accumulation. Here, we present the current understandings of chaperone biology and examine the literature investigating these proteins in the context of AD.

Show MeSH
Related in: MedlinePlus