Specific association of small heat shock proteins with the pathological hallmarks of Alzheimer's disease brains

The small heat shock protein family (sHsp) comprises molecular chaperones able to interact with incorrectly folded proteins. Alzheimer's disease (AD) is characterized by pathological lesions such as senile plaques (SPs), cerebral amyloid angiopathy (CAA) and neurofibrillary tangles (NFTs), predominantly consisting of the incorrectly folded proteins amyloid‐β (Aβ) and tau respectively. The aim of this study was to investigate the association of the chaperones Hsp20, HspB2, αB‐crystallin and Hsp27 with the pathological lesions of AD brains. For this purpose, a panel of well‐characterized antibodies directed against these sHsps was used in immunohistochemistry and immunoblotting. We observed extracellular expression of Hsp20, Hsp27 and HspB2 in classic SPs, and Hsp20 expression in diffuse SPs. In addition, extracellular expression of HspB2 was observed in CAA. Both Hsp27 and αB‐crystallin were also observed in astrocytes associated with both SPs and CAA. Furthermore, none of the sHsps were observed in NFTs in AD brains. We conclude that specific sHsp species may be involved in the pathogenesis of either SPs or CAA in AD.

[1]  N. Eberhardt,et al.  Small heat shock proteins inhibit in vitro Aβ1–42 amyloidogenesis , 1997 .

[2]  P. Fraser,et al.  Review: modulating factors in amyloid-beta fibril formation. , 2000, Journal of structural biology.

[3]  H. Braak,et al.  Staging of brain pathology related to sporadic Parkinson’s disease , 2003, Neurobiology of Aging.

[4]  W. W. Jong,et al.  αB-Crystallin is present in reactive glia in Creutzfeldt-Jakob disease , 2004, Acta Neuropathologica.

[5]  R. Mayer,et al.  Ballooned neurons in several neurodegenerative diseases and stroke contain αB crystallin , 1992 .

[6]  W. D. de Jong,et al.  The mammalian small heat-shock protein Hsp20 forms dimers and is a poor chaperone. , 1998, European journal of biochemistry.

[7]  W. W. Jong,et al.  Expression of αB-crystallin in Alzheimer's disease , 1994, Acta Neuropathologica.

[8]  K. Kato,et al.  Induction of the synthesis of hsp27 and alpha B crystallin in tissues of heat-stressed rats and its suppression by ethanol or an alpha 1-adrenergic antagonist. , 1995, Journal of biochemistry.

[9]  M. Yamada,et al.  Immune reactions associated with cerebral amyloid angiopathy. , 1996, Stroke.

[10]  J. Leunissen,et al.  The human genome encodes 10 α-crystallin–related small heat shock proteins: HspB1–10 , 2003 .

[11]  C. Masters,et al.  Cytosolic beta-amyloid deposition and supranuclear cataracts in lenses from people with Alzheimer's disease. , 2003, Lancet.

[12]  M. Waye,et al.  Muscle Develops a Specific Form of Small Heat Shock Protein Complex Composed of MKBP/HSPB2 and HSPB3 during Myogenic Differentiation* , 2000, The Journal of Biological Chemistry.

[13]  T. Iwaki,et al.  Identification and characterization of the gene encoding a new member of the alpha-crystallin/small hsp family, closely linked to the alphaB-crystallin gene in a head-to-head manner. , 1997, Genomics.

[14]  Nutan Sharma,et al.  TorsinA and heat shock proteins act as molecular chaperones: suppression of α‐synuclein aggregation , 2002, Journal of neurochemistry.

[15]  R. Mayer,et al.  αB crystallin expression in nonlenticular tissues and selective presence in ubiquitinated inclusion bodies in human disease , 1992, The Journal of pathology.

[16]  Xudong Huang,et al.  Cytosolic β-amyloid deposition and supranuclear cataracts in lenses from people with Alzheimer's disease , 2003, The Lancet.

[17]  O. Kozawa,et al.  HSP20, low-molecular-weight heat shock-related protein, acts extracellularly as a regulator of platelet functions: a novel defense mechanism. , 2002, Life sciences.

[18]  R. Roos,et al.  Hereditary cerebral hemorrhage with amyloidosis (Dutch): a model for congophilic plaque formation without neurofibrillary pathology , 2004, Acta Neuropathologica.

[19]  G. Getz,et al.  Isoform-specific binding of apolipoprotein E to beta-amyloid. , 1994, The Journal of biological chemistry.

[20]  J. Trojanowski,et al.  A68: a major subunit of paired helical filaments and derivatized forms of normal Tau. , 1991, Science.

[21]  C. Cotman,et al.  beta-Amyloid activates complement by binding to a specific region of the collagen-like domain of the C1q A chain. , 1994, Journal of immunology.

[22]  D. Ciocca,et al.  Serological detection of heat shock protein hsp27 in normal and breast cancer patients. , 1998, Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology.

[23]  R. Mayer,et al.  Ballooned neurons in several neurodegenerative diseases and stroke contain alpha B crystallin. , 1992, Neuropathology and applied neurobiology.

[24]  P. Fraser,et al.  Review: Modulating Factors in Amyloid-β Fibril Formation , 2000 .

[25]  W. D. de Jong,et al.  Expression of alpha B-crystallin in Alzheimer's disease. , 1994, Acta neuropathologica.

[26]  J. Wegiel,et al.  Ultrastructural studies of the cells forming amyloid in the cortical vessel wall in Alzheimer's disease , 2004, Acta Neuropathologica.

[27]  Jack Liang.  Interaction between β‐amyloid and lens αB‐crystallin , 2000 .

[28]  M. Gaestel,et al.  Increased expression of heat‐shock protein 27 kDa in Alzheimer disease: a preliminary study , 1993, Neuroreport.

[29]  N. Eberhardt,et al.  Small heat shock proteins inhibit in vitro A beta(1-42) amyloidogenesis. , 1997, FEBS letters.

[30]  S. Greenberg,et al.  Vascular Changes in Iowa‐Type Hereditary Cerebral Amyloid Angiopathy , 2002, Annals of the New York Academy of Sciences.

[31]  T. Iwaki,et al.  Identification and Characterization of the Gene Encoding a New Member of the α-Crystallin/Small hsp Family, Closely Linked to the αB-Crystallin Gene in a Head-to-Head Manner , 1997 .

[32]  K. Kato,et al.  Purification and characterization of a 20-kDa protein that is highly homologous to alpha B crystallin. , 1994, The Journal of biological chemistry.

[33]  G. Glenner,et al.  Alzheimer's disease: initial report of the purification and characterization of a novel cerebrovascular amyloid protein. , 1984, Biochemical and biophysical research communications.

[34]  T. Wisniewski,et al.  Accumulation of alpha B-crystallin in central nervous system glia and neurons in pathologic conditions. , 1992, The American journal of pathology.

[35]  G. Stein,et al.  Sequence and organization of genes encoding the human 27 kDa heat shock protein. , 1986, Nucleic acids research.

[36]  J. Leunissen,et al.  The human genome encodes 10 alpha-crystallin-related small heat shock proteins: HspB1-10. , 2003, Cell stress & chaperones.

[37]  W. D. de Jong,et al.  The Small Heat-shock Protein αB-Crystallin Promotes FBX4-dependent Ubiquitination* , 2003, The Journal of Biological Chemistry.

[38]  J. Trojanowski,et al.  Expression of the small heat-shock protein alphaB-crystallin in tauopathies with glial pathology. , 2004, The American journal of pathology.

[39]  J. Buchner.  Supervising the fold: functional principles of molecular chaperones , 1996, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[40]  J. Wegiel,et al.  Beta-amyloid formation by myocytes of leptomeningeal vessels. , 1994, Acta neuropathologica.

[41]  W. Boelens,et al.  Expression of small heat shock proteins HspB2, HspB8, Hsp20 and cvHsp in different tissues of the perinatal developing pig. , 2003, European journal of cell biology.

[42]  Sung-Hou Kim,et al.  Crystal structure of a small heat-shock protein , 1998, Nature.

[43]  Kenneth S. Kosik,et al.  Binding of Tau to Heat Shock Protein 27 Leads to Decreased Concentration of Hyperphosphorylated Tau and Enhanced Cell Survival* , 2004, Journal of Biological Chemistry.

[44]  W. D. de Jong,et al.  alpha B-crystallin is present in reactive glia in Creutzfeldt-Jakob disease. , 1992, Acta neuropathologica.

[45]  J. Liang.  Interaction between beta-amyloid and lens alphaB-crystallin. , 2000, FEBS letters.

[46]  M. Verbeek,et al.  Differences between the pathogenesis of senile plaques and congophilic angiopathy in Alzheimer disease. , 1997, Journal of Neuropathology and Experimental Neurology.

[47]  J Carter,et al.  Molecular Pathology of Alzheimer's Disease , 2013 .

[48]  A. Rubio,et al.  Phenotypic variability of CADASIL and novel morphologic findings , 1997, Acta Neuropathologica.

[49]  W. W. Jong,et al.  Expression of small heat-shock protein hsp 27 in reactive gliosis in Alzheimer disease and other types of dementia , 1994, Acta Neuropathologica.

[50]  W. D. de Jong,et al.  The small heat-shock protein alpha B-crystallin promotes FBX4-dependent ubiquitination. , 2003, The Journal of biological chemistry.

[51]  S. M. Sumi,et al.  The Consortium to Establish a Registry for Alzheimer's Disease (CERAD) , 1991, Neurology.