Skip to main content
Article thumbnail
Location of Repository

Exploiting the Diversity of the Heat-Shock Protein Family for Primary and Secondary Tauopathy Therapeutics

By Jose F Abisambra, Umesh K Jinwal, Jeffrey R Jones, Laura J Blair, John Koren and Chad A Dickey


The heat shock protein (Hsp) family is an evolutionarily conserved system that is charged with preventing unfolded or misfolded proteins in the cell from aggregating. In Alzheimer’s disease, extracellular accumulation of the amyloid β peptide (Aβ) and intracellular aggregation of the microtubule associated protein tau may result from mechanisms involving chaperone proteins like the Hsps. Due to the ability of Hsps to regulate aberrantly accumulating proteins like Aβ and tau, therapeutic strategies are emerging that target this family of chaperones to modulate their pathobiology. This article focuses on the use of Hsp-based therapeutics for treating primary and secondary tauopathies like Alzheimer’s disease. It will particularly focus on the pharmacological targeting of the Hsp70/90 system and the value of manipulating Hsp27 for treating Alzheimer’s disease

Topics: Article
Publisher: Bentham Science Publishers
OAI identifier:
Provided by: PubMed Central

Suggested articles


  1. (1991). A 25-kD inhibitor of actin polymerization is a low molecular mass heat shock protein.
  2. (1999). A role for HSP27 in sensory neuron survival.
  3. (1999). A role for p38(MAPK)/HSP27 pathway in smooth muscle cell migration.
  4. (1997). A small heat shock protein stably binds heat-denatured model substrates and can maintain a substrate in a folding-competent state. EMBO J,
  5. Administration of brain-derived neurotrophic factor suppresses the expression of heat shock protein 27 in rat retinal ganglion cells following axotomy.
  6. Akt and CHIP coregulate tau degradation through coordinated interactions.
  7. (1993). Alpha B crystallin and HSP28 are enhanced in the cerebral cortex of patients with Alzheimer's disease.
  8. (1997). Alzheimer's disease: genotypes, phenotypes, and treatments. Science,
  9. (2008). Amyloid-beta protein dimers isolated directly from Alzheimer's brains impair synaptic plasticity
  10. (2003). Analysis of the interaction of small heat shock proteins with unfolding proteins.
  11. (2005). Atorvastatin and myocardial reperfusion injury: new pleiotropic effect implicating multiple prosurvival signaling.
  12. (2007). BAG-1 associates with Hsc70. Tau complex and regulates the proteasomal degradation of Tau protein.
  13. (1997). Basolateral membrane-associated 27-kDa heat shock protein and microfilament polymerization.
  14. (2000). Benign focal ischemic preconditioning induces neuronal Hsp70 and prolonged astrogliosis with expression of Hsp27. Brain Res.,
  15. (2009). Bicyclol: a novel drug for treating chronic viral hepatitis B
  16. (1997). Binding of non-native protein to Hsp25 during heat shock creates a reservoir of folding intermediates for reactivation.
  17. (2004). Binding of tau to heat shock protein 27 leads to decreased concentration of hyperphosphorylated tau and enhanced cell survival.
  18. (2008). Blocking Abeta42 accumulation delays the onset and progression of tau pathology via the C terminus of heat shock protein70-interacting protein: a mechanistic link between Abeta and tau
  19. (2004). Celastrols as inducers of the heat shock response and cytoprotection.
  20. (1994). Cells overexpressing Hsp27 show accelerated recovery from heat-induced nuclear protein aggregation.
  21. (2004). Chaperone activity of cytosolic small heat shock proteins from wheat.
  22. (2003). Chaperones increase association of tau protein with microtubules.
  23. (1988). Characterization of an inhibitor of actin polymerization in vinculin-rich fraction of turkey gizzard smooth muscle.
  24. (2009). Chemical manipulation of hsp70 ATPase activity regulates tau stability.
  25. (2007). CHIP and HSPs interact with beta-APP in a proteasome-dependent manner and influence Abeta metabolism.
  26. (2004). CHIP-Hsc70 complex ubiquitinates phosphorylated tau and enhances cell survival.
  27. (2000). Constitutive expression of the 25-kDa heat shock protein Hsp25 reveals novel parasagittal bands of purkinje cells in the adult mouse cerebellar cortex.
  28. (1997). Constitutive expression of the 27-kDa heat shock protein (Hsp27) in sensory and motor neurons of the rat nervous system.
  29. (1997). Cortical application of potassium chloride induces the low-molecular weight heat shock protein (Hsp27) in astrocytes.
  30. (1994). Dephosphorylation of the small heat shock protein Hsp27 in vivo by protein phosphatase 2A.
  31. (2002). Differential effect of simvastatin on activation of Rac(1) vs. activation of the heat shock protein 27-mediated pathway upon oxidative stress, in human smooth muscle cells.
  32. (1988). Dynamic changes in the structure and intracellular locale of the mammalian low-molecularweight heat shock protein.
  33. (1998). Evidence for a hsp25-specific mechanism involved in transcriptional activation by heat shock.
  34. (2011). Exploiting the Diversity of the Heat-Shock Protein Current Neuropharmacology,
  35. (2001). Expression of heat-shock protein Hsp25 in mouse Purkinje cells during development reveals novel features of cerebellar compartmentation.
  36. (1994). Expression of small heat-shock protein hsp 27 in reactive gliosis in Alzheimer disease and other types of dementia.
  37. (1996). Expression of the 27,000 mol. wt heat shock protein following kainic acid-induced status epilepticus in the rat. Neuroscience,
  38. Expression of the small heat-shock protein alphaBcrystallin in tauopathies with glial pathology.
  39. (2006). Expression profiles for macrophage alternative activation genes in AD and in mouse models of
  40. (2009). Facilitating Akt clearance via manipulation of Hsp70 activity
  41. (1983). Formation of cytoplasmic heat shock granules in tomato cell cultures and leaves. Mol. Cell Biol.,
  42. Four small Drosophila heat shock proteins are related to each other and to mammalian alpha-crystallin.
  43. (2004). Gene expression profiling in fetal, aged, and Alzheimer hippocampus: a continuum of stress-related signaling.
  44. (1998). Genetic dissection of Alzheimer's disease and related dementias: amyloid and its relationship to tau.
  45. (2003). Heat shock protein 27 delivered via a herpes simplex virus vector can protect neurons of the hippocampus against kainic-acid-induced cell loss. Brain Res.
  46. (2009). Heat shock protein 27 phosphorylation: kinases, phosphatases, functions and pathology. Cell Mol. Life Sci.,
  47. (2001). Heat shock protein 27 shows a distinctive widespread spatial and temporal pattern of induction in CNS glial and neuronal cells compared to heat shock protein 70 and caspase 3 following kainate administration. Brain Res.
  48. (2000). Heat shock proteins Hsp27 and Hsp32 localize to synaptic sites in the rat cerebellum following hyperthermia. Brain Res.
  49. (2007). Heat Shock Proteins: Expression and functional roles in nerve cells and glia. In: Richter-Landsberg,
  50. (2002). Heat-shock protein 90 inhibitors as novel cancer chemotherapeutic agents.
  51. (1988). Homologous plant and bacterial proteins chaperone oligomeric protein assembly. Nature,
  52. (2010). Hsc70 rapidly engages tau after microtubule destabilization.
  53. (2006). HSP induction mediates selective clearance of tau phosphorylated at prolinedirected Ser/Thr sites but not
  54. (2001). Hsp25 and -90 immunoreactivity in the normal rat eye.
  55. (1999). HSP27 multimerization mediated by phosphorylation-sensitive intermolecular interactions at the amino terminus.
  56. (2008). Hsp27 protects against ischemic brain injury via attenuation of a novel stress-response cascade upstream of mitochondrial cell death signaling.
  57. (2002). Hsp27 upregulation and phosphorylation is required for injured sensory and motor neuron survival. Neuron,
  58. (2000). Hsp70 and hsp40 chaperones can inhibit self-assembly of polyglutamine proteins into amyloid-like fibrils.
  59. (2000). Hyperthermic induction of the 27-kDa heat shock protein (Hsp27) in neuroglia and neurons of the rat central nervous system.
  60. (2007). Impaired migration of trophoblast cells caused by simvastatin is associated with decreased membrane
  61. (1993). Increased expression of heat-shock protein 27 kDa in Alzheimer disease: a preliminary study.
  62. (1994). Induction of 27-kDa heat shock protein following cerebral ischemia in a rat model of ischemic tolerance. Brain Res.,
  63. (1993). Induction of Chinese hamster HSP27 gene expression in mouse cells confers resistance to heat shock. HSP27 stabilization of the microfilament organization.
  64. (2003). Induction of Hsp27 and Hsp32 stress proteins and vimentin in glial cells of the rat hippocampus following hyperthermia.
  65. (1998). Induction of the 27-kDa heat shock protein (Hsp27) in the rat medulla oblongata after vagus nerve injury.
  66. (2002). Injury to retinal ganglion cells induces expression of the small heat shock protein Hsp27 in the rat visual system. Neuroscience,
  67. MAP kinase activation by vascular endothelial growth factor mediates actin reorganization and cell migration in human endothelial cells.
  68. (2003). Mechanism of simvastatin on induction of heat shock protein in osteoblasts.
  69. (1986). Microtubule-associated protein tau (tau) is a major antigenic component of paired helical filaments in Alzheimer disease.
  70. (1986). Microtubule-associated protein tau. A component of Alzheimer paired helical filaments.
  71. (1993). Modulation of actin microfilament dynamics and fluid phase pinocytosis by phosphorylation of heat shock protein 27.
  72. Modulation of cellular thermoresistance and actin filament stability accompanies phosphorylation-induced changes in the oligomeric structure of heat shock protein 27.
  73. (2007). Molecular chaperone-mediated tau protein metabolism counteracts the formation of granular tau oligomers in human
  74. (2002). Molecular chaperones--cellular machines for protein folding.
  75. (1997). Molecular characterization of a small heat shock/alpha-crystallin protein in encysted Artemia embryos.
  76. (2004). Mutant small heat-shock protein 27 causes axonal Charcot-MarieTooth disease and distal hereditary motor neuropathy.
  77. (2002). Naturally secreted oligomers of amyloid beta protein potently inhibit hippocampal longterm potentiation in vivo. Nature,
  78. (1993). Neurodegeneration induced by beta-amyloid peptides in vitro: the role of peptide assembly
  79. Neuronal expression of constitutive heat shock proteins: implications for neurodegenerative diseases.
  80. (2006). Neuroprotective effects of virally delivered HSPs in experimental stroke.
  81. (2006). Opposing activities protect against age-onset proteotoxicity. Science,
  82. (2006). Pharmacologic reductions of total tau levels; implications for the role of microtubule dynamics in regulating tau expression.
  83. (2009). Phosphoproteome study reveals Hsp27 as a novel signaling molecule involved in GDNF-induced neurite
  84. (1994). Phosphorylated HSP27 associates with the activation-dependent cytoskeleton in human platelets.
  85. (1994). Phosphorylation and supramolecular organization of murine small heat shock protein HSP25 abolish its actin polymerization-inhibiting activity.
  86. Phosphorylation dynamics regulate Hsp27-mediated rescue of neuronal plasticity deficits in tau transgenic mice.
  87. (1999). Protection of neuronal cells from apoptosis by Hsp27 delivered with a herpes simplex virus-based vector.
  88. Protein changes in senile dementia.
  89. (2002). Protein quality control: Ubox-containing E3 ubiquitin ligases join the fold. Trends Biochem. Sci.,
  90. (1987). Proteins as molecular chaperones.
  91. (2004). Proteolytic stress causes heat shock protein induction, tau ubiquitination, and the recruitment of ubiquitin to tau-positive aggregates in oligodendrocytes in culture.
  92. (1998). Repression of heat shock transcription factor HSF1 activation by HSP90 (HSP90 complex) that forms a stress-sensitive complex with HSF1. Cell,
  93. (2007). Roles of heatshock protein 90 in maintaining and facilitating the neurodegenerative phenotype in tauopathies.
  94. (2006). Simvastatin promotes heat shock protein 27 expression and Akt activation in the rat retina and protects axotomized retinal ganglion cells in vivo.
  95. (1999). Site-directed spin labeling study of subunit interactions in the alpha-crystallin domain of small heat-shock proteins.
  96. (1997). Site-directed spin-labeling study of the structure and subunit interactions along a conserved sequence in the alpha-crystallin domain of heat-shock protein 27. Evidence of a conserved subunit interface. Biochemistry,
  97. (1993). Small heat shock proteins are molecular chaperones.
  98. (2006). Small heat shock proteins differentially affect Abeta aggregation and toxicity.
  99. (2008). Small heat shock proteins Hsp27 or alphaBcrystallin and the protein components of neurofibrillary tangles: tau and neurofilaments.
  100. (2006). Small heat shock proteins inhibit amyloid-beta protein aggregation and cerebrovascular amyloid-beta protein toxicity. Brain Res.,
  101. (1997). Small heat shock proteins inhibit in vitro A beta(1-42) amyloido- genesis. FEBS Lett.,
  102. (2000). Small heat shock proteins, the cytoskeleton, and inclusion body formation.
  103. (1999). Small stress protein Hsp27 accumulation during dopamine-mediated differentiation of rat olfactory neurons counteracts apoptosis. Cell Death Differ,
  104. (1996). Small stress proteins as novel regulators of apoptosis. Heat shock protein 27 blocks Fas/APO-1- and staurosporine-induced cell death.
  105. (2005). Some like it hot: the structure and function of small heat-shock proteins.
  106. (2006). Specific association of small heat shock proteins with the pathological hallmarks of Alzheimer's disease brains.
  107. (2004). Statin therapy and risk of dementia in the elderly: a community-based prospective cohort study. Neurology,
  108. (2005). Statin use and the risk of incident dementia: the Cardiovascular Health Study.
  109. (2000). Statins and the risk of dementia. Lancet,
  110. (2008). Statins modulate heat shock protein expression and enhance retinal ganglion cell survival after transient retinal ischemia/reperfusion in vivo.
  111. (2005). Tau suppression in a neurodegenerative mouse model improves memory function. Science,
  112. (2004). Tau-inclusion body formation in oligodendroglia: the role of stress proteins and proteasome inhibition.
  113. The alternative conformations of amyloidogenic proteins and their multi-step assembly pathways.
  114. (2009). The cochaperone BAG2 sweeps paired helical filament- insoluble tau from the microtubule.
  115. (1999). The dynamics of Hsp25 quaternary structure. Structure and function of different oligomeric species.
  116. (2007). The high-affinity HSP90-CHIP complex recognizes and selectively degrades phosphorylated tau client proteins.
  117. (2002). The impact of the use of statins on the prevalence of dementia and the progression of cognitive impairment.
  118. (1987). The precursor of Alzheimer's disease amyloid A4 protein resembles a cell-surface receptor. Nature,
  119. (2005). The role of heat shock proteins
  120. (2009). The small heat shock protein Hsp27 protects cortical neurons against the toxic effects of beta-amyloid peptide.
  121. (2008). Transduced human PEP-1-heat shock protein 27 efficiently protects against brain ischemic insult.
  122. (2008). Two motifs within the tau microtubule-binding domain mediate its association with the hsc70 molecular chaperone.
  123. (2002). Use of lipid-lowering agents, indication bias, and the risk of dementia in communitydwelling elderly people.
  124. (2008). What do we know about the long-term consequences of stress on ageing and the progression of age-related neurodegenerative disorders?

To submit an update or takedown request for this paper, please submit an Update/Correction/Removal Request.