Journal of Syndromes

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Research Article

The Role of Heat Shock Proteins in Alzheimer Disease: A Systematic Review

Mohammad Reza Najarzadegan1, Elham Ataei2, Farzad Akbarzadeh3, Mahdieh borhani3, Naghmeh Mokhber3 and Mohammad Kiani3*

  • 1Tehran Institute of Psychiatry, Faculty of Behavioral Sciences and Mental Health, Iran University of Medical Sciences, Tehran, Iran
  • 2Iranshahr University of medical sciences, Iranshahr, Iran
  • 3Psychiatry and Behavioral Sciences Research Center, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran

*Address for Correspondence: Mohammad Kiani, Psychiatry and Behavioral Sciences Research Center, Mashhad University of Medical Sciences, Mashhad, Iran, Tel: +989131279365; E-mail:
Najarzadegan MR, Ataei E, Akbarzadeh F, borhani M, Mokhber N, et al. The Role of Heat Shock Proteins in Alzheimer Disease: A Systematic Review. J Syndromes. 2016;3(1): 6.
Copyright © 2016 Kiani et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Journal of Syndromes | ISSN: 2380-6036 | Volume: 3, Issue: 1
Submission: 06 April, 2016 | Accepted: 03 May, 2016 | Published: 09 May, 2016
Reviewed & Approved by:
Dr. Tushar Patil, Department of Neurology, Jawaharlal Nehru Medical College, Wardha, India


Background: Recent studies have shown that heat shock proteins (HSPs) play a role in pathogenesis of Alzheimer’s disease.

Objectives: In this review article we investigated the role of HSPs in pathogenesis of cognitive disorders such as Alzheimer’s disease.

Data sources: We have reviewed publications from the electronic databases of Medline/PubMed, Scopus, Google Scholar, Embase, ISI Web of Knowledge, Biological Abstracts and Chemical Abstracts with keywords of Heat Shock Protein (HSP), Neurocognitive disorders, Alzheimer’s disease and Dementia.

Study eligibility criteria: 

After search of data basis with above keywords we found 337 papers published. Then we narrowed our findings to 40 articles and reviewed them.

Results: Results of our study showed that heat shock proteins (HSPs) help refold or degrade mis-folded proteins, reduce abnormal protein accumulation and dysfunction of synapses, neuronal degeneration and gradual and continuous loss of cognitive function in Alzheimer’s disease and improves the associated symptoms.

Limitations: We reviewed only some electronic database and other literatures were not reviewed. Conclusion: Heat shock proteins (HSPs) have significant role in pathogenesis of Alzheimer’s disease and other causes of dementia.


Heat shock protein; Neurocognitive disorders; Alzheimer’s disease; Dementia


Dementia is a disorder that is characterized by impairment of memory and at least one other cognitive function such as aphasia,apraxia, agnosia and loss of executive function. These caused loss of previous level of function [1]. Alzheimer disease (AD) is the most common form of dementia in the elderly, and causes 60 to 80 percent of dementia in elderly [2-4].

Heat shock proteins (HSP) are a group of proteins that impressed by heat shock, the subgroup of these proteins are related proteins functionally take part in the folding and unfolding of other proteins. Their expression is increased in high temperatures or other stress that cells are exposed [5]. The upregulation of the heat shock proteins is important to the heat shock response and is induced by heat shock factor (HSF) [6]. Heat shock proteins are named by their molecular weight. For example, HSP60 has 60 kilodaltons (kd) molecular weight [7].

Recent studies have shown that these proteins have an important role in the pathogenesis of Alzheimer’s disease. For example, HSP 70 family has been involved in the pathology of Alzheimer’s disease and its major clinical and pathological characteristics like neurofibrillary tangles and β-amyloid [8-10]. Aβ plaques are important in pathogenesis of Alzheimer’s disease and they are mis-folded proteins, because Alzheimer’s disease is an example of disorder in proteinfolding [8-10]. HSPs are the important chaperones for reconciliation of proper folding of proteins [11].

On the other hand, small heat shock proteins like HSP27 ubiquitin, α-crystallin, HSP20 and others have chaperone activity, thermotolerance, inhibition of apoptosis, regulation of cell development, and cell differentiation. They also have signal transduction effect [12]. HSP27 provide thermotolerance, cytoprotection, and in time of stressful conditions support the cell survival. HSP27 also works as a chaperone independent with ATP and partially stabilized denatured proteins and also inhibit aggregation of proteins which ensures refolding by the HSP70-complex and involved in the apoptotic signaling pathway. HSP27 interacts with the outer mitochondrial membrane and inhibits the activation of procaspase-9 [13]. The phosphorylated form of HSP27 inhibits Daxx apoptotic protein and with Fas and Ask1, it prevents the association of Daxx [14].

There is increasing evidence for the involvement of the heat shock proteins family in neurodegenerative disorders. It has been shown that Aβ plaques and HSP70 are localized together [15]. Recent evidence suggests that HSP70 suppresses formation of NFTs with enhanced tau solubility and tau binding to microtubules [16]. Control of the response of cells to stress involving induction of HSPs in differentiated neurons gives a potential therapeutic method to make changes in neuronal proteins that start pathogenic cascades resulting in human neurodegenerative disorders. Given that the etiology of Alzheimer’s disease is still unknown, the understanding of HSPs role in Alzheimer’s disease and other cognitive disorders can help much more to understanding the etiology and treatment of Alzheimer’s disease. In this review article, we investigated the role of proteins in pathogenesis of cognitive disorders such as Alzheimer’s disease.


All published studies concerning HSP and Neurocognitive disorders and Alzheimer disease were included from 1970 until 2014 January. Publications were identified from the following electronic databases: Medline/PubMed, Scopus, Google Scholar, Embase, ISI Web of Knowledge, Biological Abstracts and Chemical Abstracts.

Study eligibility criteria

To include all of studies in electronic databases, keywords such as Heat Shock Protein (HSP); Neurocognitive disorders; Alzheimer disease; Dementia were used. After search of database with above keywords we found 337 papers published. Then we narrowed our findings to 40 articles and reviewed them. Subsequently, the therapeutic approaches to Alzheimer disease and the role of HSPs were analyzed.

The criteria for Alzheimer disease are shown in Table 1.


Table 1: Criteria for Alzheimer’s disease (from DSM-IV-TR) [41].


We investigated the previous studies on role of HSPs in Alzheimer disease and other causes of dementia. The results are shown in Table 2


Table 2: Results of studies on role of HSPs in Alzheimer disease and other causes of dementia.


Alzheimer’s disease is a progressive neurodegenerative disorder characterized by loss of memory and cognition and by pathological lesions such as senile plaques, cerebral amyloid angiopathy and neurofibrillary tangles, predominantly consisting of the incorrectly folded proteins amyloid-beta and tau respectively [24]. Amyloid-beta peptide is a main element of senile plaques and has an important role to pathogenesis of the disease [28]. The heat shock proteins constitute molecular chaperones able to act with proteins that are folded incorrectly. It has been shown that impaired protein folding and related decrease in protein function is important factor in the process of neurodegeneration [27]. HSPs play some other roles in the body. For example HSP70 acts as a damage-associated molecular pattern; activates and regulates signaling cascades [29,30] and acts on neurons and numerous cell types. We reviewed the literature role of proteins in the pathogenesis of cognitive disorders such as Alzheimer’s disease.

This review showed that expression of HSP can be related to the severity and duration of symptoms of Alzheimer’s disease. Study of Renkawek et al. showed the highest expression of wherever rich in terms of senile plaques, Hirano bodies, neurofibrillary tangles as well as in some hippocampal neurons, degenerative astrocytes demonstrated the highest expression of HSP27 [31]. Also, severity of AD and period of lasting dementia led to an increase of HSP27 expression. Thus we can conclude that higher expression of HSP27 is related to AD pathology, especially in astrocytes.

It is proved that HSPs make some contributions to neuronal survival and communication which exists between glial cells and neurons. In a study by May et al. it was found that glial cells are capable of providing HSP70 to neurons and that when faced with stress, neurons have a limited ability to generate HSP70 [32]. The ability of HSPs to defend nervous system against various stress and neurodegenerative diseases was known previously [33-35]. Another study by Guzhova et al. showed that it is possible to transfer HSP70 from adjacent glial cells to axons, it was also revealed that extracellular HSP70 is able to defend motor neurons [36]. Additionally, a study by Prahlad V et al. indicated that heat-sensing neurons would prevent heat shock response to be implanted with chronic stress. Moreover, HSP70 not only saves vital components of the cell, but also saves the cell in general [37]. It hampers apoptosis and raises the chances of cells’ survival along with improving cell’s proteins integration [38,39].

The study of Hoshino et al. showed that HSPs caused expression of a growth factor that activates phagocytosis by microglia named A-degrading enzyme that is a marker of microglial activation and it increased overexpression of reduced plaque formation and neuronal and synaptic loss in Alzheimer’s disease [40,41].


We reviewed only some electronic database and other literatures were not reviewed.


This review showed that heat shock proteins (HSPs) help refold or degrade mis-folded proteins, reduce abnormal protein accumulation and synaptic dysfunction, neuronal degeneration and cognitive decline in Alzheimer’s disease and improves the associated symptoms.



This study was supported with Behavioral Science Research Centre of Mashhad University of Medical Science, Mashhad, Iran. The authors had no conflict of interests and they approved this paper.


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