Molecular Neurobiology

, Volume 53, Issue 2, pp 905–931 | Cite as

The Ubiquitin-Proteasome System and Molecular Chaperone Deregulation in Alzheimer’s Disease

  • Yanuar Alan Sulistio
  • Klaus HeeseEmail author


One of the shared hallmarks of neurodegenerative diseases is the accumulation of misfolded proteins. Therefore, it is suspected that normal proteostasis is crucial for neuronal survival in the brain and that the malfunction of this mechanism may be the underlying cause of neurodegenerative diseases. The accumulation of amyloid plaques (APs) composed of amyloid-beta peptide (Aβ) aggregates and neurofibrillary tangles (NFTs) composed of misfolded Tau proteins are the defining pathological markers of Alzheimer’s disease (AD). The accumulation of these proteins indicates a faulty protein quality control in the AD brain. An impaired ubiquitin-proteasome system (UPS) could lead to negative consequences for protein regulation, including loss of function. Another pivotal mechanism for the prevention of misfolded protein accumulation is the utilization of molecular chaperones. Molecular chaperones, such as heat shock proteins (HSPs) and FK506-binding proteins (FKBPs), are highly involved in protein regulation to ensure proper folding and normal function. In this review, we elaborate on the molecular basis of AD pathophysiology using recent data, with a particular focus on the role of the UPS and molecular chaperones as the defensive mechanism against misfolded proteins that have prion-like properties. In addition, we propose a rational therapy approach based on this mechanism.


Alzheimer’s disease Ubiquitin-proteasome system Amyloid-beta Tau protein FKBP Prion-like transmission 



Amino acid


Alzheimer’s disease


A disintegrin and metalloproteinase




APP intracellular c-terminal domain


Amyotrophic lateral sclerosis


AMP-activated kinase


Amyloid plaque


Anterior pharynx-defective 1


Apolipoprotein E4


Amyloid precursor protein

Amyloid-beta peptide


Beta-site APP cleaving enzyme 1


Calcium/calmodulin-dependent protein kinase II


Cyclin-dependent kinase 5


Carboxyl terminus of HSP70-interacting protein




Creutzfeldt-Jakob disease


Casein kinase II


Central nervous system


Cerebrospinal fluid


Cu(II)-binding domain


Dementia with Lewy bodies


Dual-specificity tyrosine-regulated kinase 1A


Epidermal growth factor receptor


Early-onset AD


Endoplasmic reticulum


FK506-binding domain


FK506-binding protein


Frontotemporal dementia related to chr 17


Heparin-binding domain


Huntington’s disease


Heat shock protein


Intrinsically disordered protein


Kunitz-type serine protease inhibitor


Late-onset AD


Lipoprotein receptor-related protein 1


Long-term potentiation


Microtubule-associated protein


Mitogen-activated protein kinase


Microtubule-associated protein Tau


MAP/microtubule-affinity-regulating kinases


Magnetic resonance imaging


Neurofibrillary tangle


Notch intracellular domain


Neural precursor cell


Parkinson’s disease


Presenilin enhancer 2


Paired helical filament


Peptidyl-prolyl cis/trans isomerase NIMA-interacting 1


Protein kinase A


Protein kinase C


Prion protein




Regulated intramembrane proteolysis


Reticulon family protein


Superoxide dismutase 1


Subventricular zone


Tumor necrosis factor-α converting enzyme


Transient axonal glycoprotein


Tau aggregation inhibitor


TAR DNA-binding protein-43


Trans-Golgi network


Tripartite motif


Ubiquitin B


Ubiquitin C


Ubiquitin-proteasome system



This work was supported by the research fund of Hanyang University.

Conflict of Interest

The authors declare that they have no conflict of interest.


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© Springer Science+Business Media New York 2014

Authors and Affiliations

  1. 1.Graduate School of Biomedical Science and EngineeringHanyang UniversitySeongdong-guRepublic of Korea

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