Elsevier

Progress in Neurobiology

Volume 155, August 2017, Pages 171-193
Progress in Neurobiology

Review Article
Protein aggregation and neurodegeneration in prototypical neurodegenerative diseases: Examples of amyloidopathies, tauopathies and synucleinopathies

https://doi.org/10.1016/j.pneurobio.2015.07.003Get rights and content

Highlights

  • β-Amyloid peptide-containing plaques and intraneuronal neurofibrillary tangles composed of hyperphosphorylated microtubule-associated protein tau are the two main neuropathological in Alzheimer's disease.

  • Parkinson's disease is defined by the presence of Lewy Bodies that are intraneuronal proteinaceous cytoplasmic inclusions.

  • α-Synuclein has been identified as a major protein component of Lewy Bodies and heavily implicated in the pathogenesis of Parkinson's disease.

  • Aβ, tau and α-syn share common pathological features regarding structure, aggregation and spreading properties.

Abstract

Alzheimer's and Parkinson's diseases are the most prevalent neurodegenerative diseases that generate important health-related direct and indirect socio-economic costs. They are characterized by severe neuronal losses in several disease-specific brain regions associated with deposits of aggregated proteins. In Alzheimer's disease, β-amyloid peptide-containing plaques and intraneuronal neurofibrillary tangles composed of hyperphosphorylated microtubule-associated protein tau are the two main neuropathological lesions, while Parkinson's disease is defined by the presence of Lewy Bodies that are intraneuronal proteinaceous cytoplasmic inclusions. α-Synuclein has been identified as a major protein component of Lewy Bodies and heavily implicated in the pathogenesis of Parkinson's disease. In the past few years, evidence has emerged to explain how these aggregate-prone proteins can undergo spontaneous self-aggregation, propagate from cell to cell, and mediate neurotoxicity. Current research now indicates that oligomeric forms are probably the toxic species. This article discusses recent progress in the understanding of the pathogenesis of these diseases, with a focus on the underlying mechanisms of protein aggregation, and emphasizes the pathophysiological molecular mechanisms leading to cellular toxicity. Finally, we present the putative direct link between β-amyloid peptide and tau in causing toxicity in Alzheimer's disease as well as α-synuclein in Parkinson's disease, along with some of the most promising therapeutic strategies currently in development for those incurable neurodegenerative disorders.

Introduction

The continuing demographic shift of population toward an older society has led to a growing prevalence of chronic age-related diseases in all industrialized countries. Development of degenerative diseases, such as Alzheimer's disease (AD), associated with neurodegeneration, impaired synaptic function, and massive brain cell loss, loss of cognitive ability and premature death (Holscher, 1998), has a major impact on health along with economical ramifications in Western world. The socioeconomic impact of AD worldwide is immense, even though it is difficult to provide an exact estimation. AD is the fourth main cause of death affecting more than 35 million people worldwide and it is projected to almost quadruple by 2050 (Ferri et al., 2005, Prince et al., 2013a) whereas the number of caregivers will rise up to 216 millions. Furthermore, the direct and indirect economic cost associated with the disease in 2010 was estimated at more than $600 billion worldwide and it is expected to rise at $1 trillion by 2030 (Prince et al., 2014), making AD and other dementias the world's “18th largest economy” (Prince et al., 2013b). The greatest economic cost of dementia is associated with providing institutional and home-based long-term care rather than direct medical services. The prevalence of dementia increases strongly with age and it is projected that the costs of dementia could more than double by 2040 as the nation's population continues to grow older, assuming that the age-specific occurrence rate of the disease remains constant (Prince et al., 2013a). The average lifespan of sufferers is between 7 and 10 years from the time of diagnosis and no cure is presently known.

The pathogenesis of AD has not yet been clarified and the understanding of the disease mechanism remains elusive. Even though the clinical symptoms of AD are usually diagnosed in older people, there are significant evidences indicating that AD-related processes and mechanisms initiate several decades before the clinical onset of the disease (Langbaum et al., 2013). Despite the immense research efforts that have been put over the past years on the characterization of AD and the development of disease-modifying therapeutic approaches, there is still no cure for AD. To date, AD can only be confirmed postmortem whereas initiation of AD pathology is estimated to start several (10–15) years prior to the onset of clinical symptoms. This makes imperative the early identification of AD and the discovery of diagnostic markers for AD (DeKosky and Marek, 2003) key factors for prevention and successful therapeutic intervention of AD. The recent advances in molecular biology, genetics, neurochemistry and imaging technologies (including new amyloid imaging agents) have provided insights of the processes involved in the pathogenesis of AD and have made possible to track amyloid pathology along with disease progression in the living patient.

Parkinson's disease (PD) affects 1.1 million persons in the EU and 6.3 million worldwide (Dowding et al., 2006). Throughout Europe, the annual burden to society including both direct and indirect costs, has been estimated at EUR 138,000 per patient (increasing 5% per year) and these findings are roughly within the same range as estimates from other developed nations (Source: JPND website) (Gammon, 2014). While drug therapy for symptom management makes up the largest portion of direct health care costs (market for drugs to treat PD had a value of EUR 1.8 billion), it accounts for only 10% of total costs as the major costs are consecutive of late stage complications and dramatic impairment of quality of life (QOL) (Dowding et al., 2006). Therefore, neuroprotective or neurorestorative strategies that would stop or slow down the yet unrelenting degenerative process are eagerly awaited as they would have a huge impact both on PD patients’ QOL and the economic burden for the society.

AD and PD share striking common features despite diverse clinical symptoms and transmission mode (Bertram and Tanzi, 2005). The hallmarks of these disorders are a selective neuronal vulnerability with degeneration in specific brain regions leading to (i) inexorable impairments of memory and cognitive functions in AD and (ii) paralysis-like syndrome in PD, and deposits of aggregated proteins of aberrant conformation (Taylor et al., 2002). The two neuropathological hallmarks of AD have been described in the original report by Alois Alzheimer (Maurer et al., 1997), as the senile plaques (SP) containing extracellular deposits of beta-amyloid peptide (Aβ), and intraneuronal neurofibrillary tangles (NFTs) composed of abnormal filaments of hyperphosphorylated microtubule-associated tau protein (Serrano-Pozo et al., 2011). Abnormal accumulation of misfolded α-synuclein (α-syn) is the pathological hallmark of several neurodegenerative diseases and forms Lewy Bodies (LB) and neurites (LN) in PD and Dementia with Lewy Bodies (DLB) or glial cytoplasmic inclusions in Multiple System Atrophy (MSA) (Goedert et al., 2013). Most notably, these diseases belong to proteinopathies, defined by the misfolding of a disease-specific protein that self-assembled into an aggregated β-sheet rich structure. Despite considerable differences in primary sequence, the pathological conformers of the disease-specific proteins share similar important structural features. The molecular mechanisms accountable for the transition from a soluble, functional, conformation to an aggregated, pathological, one are not completely understood (Soto, 2003). Quality control pathways protect cells from the deleterious effect of misfolded proteins. Molecular chaperones refold abnormally folded polypeptides or direct them to degradation machinery (Kim et al., 2013). Failure to refold or to degrade aberrant proteins leads to their aggregation (Hipp et al., 2014). Neurons, as postmitotic cells, are particularly sensitive to misfolding injury, as they cannot dilute it by means of cell division. In addition, the accumulation of aberrant proteins increases with age, when quality control might become less efficient, as illustrated both by a decreased activity of the ubiquitin/proteasome system (Dantuma and Bott, 2014) and autophagy (Cuervo and Dice, 2000, Martinez-Vicente and Cuervo, 2007). Impaired proteostasis, in combination with other cellular alterations, is believed to be responsible for the excessive aggregation of misfolded proteins in AD and PD.

The pathogenic roles of Aβ and tau in AD, as well as α-syn in PD are sustained by several lines of evidence. Research over the last twenty years has revealed and clarified the pathological pathways and mechanisms of these diseases. These changes in the disease-specific proteins are also associated with noticeable activation of inflammatory processes and increased levels of oxidative stress, inflammation, and neuronal cell death (Ballard et al., 2011, McGeer and McGeer, 2007). Nevertheless, it is difficult to determine whether the presence of these protein aggregates is rather a consequence rather than a cause. Numerous genetic, cell biology and biochemical data support the model whereby neurodegeneration is caused by a toxic gain of function of the misfolded protein. Even though, the correlation between protein aggregation and nervous system degeneration remains mostly unknown, these disease-specific aggregated proteins and peptides have apparent diagnostic and even therapeutic implications (Ross and Poirier, 2004). In AD, the prevailing hypotheses are centered on the Aβ deposits and NFTs, which have been described in patients with AD (Behl, 1999) while α-syn receives most attention in PD. It is widely considered that abnormal accumulation and aggregation of these disease-specific proteins lead to neurodegeneration; therefore these proteins have been studied extensively in order to understand the ongoing mechanisms and identify potential treatment approaches. In this review, we place these crucial questions into the context of what is currently known about the aggregation and neurodegenerative processes for these disease-related proteins.

Section snippets

General dynamics of protein aggregation in Alzheimer's disease

AD, originally described by Alois Alzheimer in 1906, involves the progressive deterioration of memory and is characterized by gradual neurodegeneration due to extensive neuronal atrophy with concomitant loss of synapses throughout different brain regions, ultimately leading to widespread brain atrophy. Even though extracellular deposits of Aβ forming SP and NFTs of hyperphosphorylated tau are associated with normal aging, these are the two main histopathological lesions found in patients with

Alzheimer's disease: amyloid-β peptide and tau

Neurodegeneration is a central feature of AD and involves synaptic damage and disruption of neuronal integrity. Various hypotheses have been proposed over the years to explain the order of pathogenic events leading to neurodegeneration. Among the prevailing hypotheses is the conversion of non-toxic Aβ monomers to toxic Aβ oligomers, accumulation at the synapses followed by structural/functional damage thereof, decrease of some postsynaptic excitatory proteins, the alteration in the number and

Disease-related protein spreading in Alzheimer's and Parkinson's diseases

Emerging evidence has strongly implicated cell-to-cell transmission of misfolded proteins as a common mechanism for the onset and progression of a bewildering variety of neurodegenerative diseases. Indeed, several studies suggested that most aggregation-prone proteins linked to neurodegenerative diseases (Prusiner, 2012), including α-syn (Desplats et al., 2009, Lee et al., 2010b, Luk et al., 2009), huntingtin (Cicchetti et al., 2014), tau (Clavaguera et al., 2009), superoxide dismutase 1 (Grad

Therapeutic approaches

In the recent years, numerous efforts have been made toward developing therapies for AD and PD. These treatment approaches interfere with the mechanisms that drive the development of the disease, i.e., they are divided into Aβ- and tau-pathology approaches for AD (Citron, 2010, Giacobini and Gold, 2013) and α-syn-based strategy for PD. In the same issue, S. Mandel and H. Steinbusch will present and discuss a thorough review on strategies preventing neurodegenerative diseases. In the next

Future perspectives

The progressive dysfunction and neuronal cell death are characteristics of the most common neurodegenerative diseases such as AD and PD. AD, the most common dementia syndrome, is a slowly progressive neurodegenerative disease of the brain that affect memory, thinking, behavior and the ability to perform everyday activities, whereas PD is primarily a movement disorder evolving later toward dementia. Even though there has been a remarkable improvement in our understanding of the pathogenesis of

Acknowledgments

The University of Bordeaux and the Centre National de la Recherche Scientifique provided infrastructural support. This work was supported by Marie Curie Reintegration Grant FP7-PEOPLE-2009-ERG256303 from the European Commission (to B.D.), by a grant from the Fondation pour la Recherche Médicale (to B.D.), by Agence Nationale de la Recherche Grants ANR-12-BSV4-0001-01 (to E.B.), and by a grant from LABEX BRAIN ANR-10-LABX-43 (to E.B.) and M.B. is a recipient of an MESR fellowship. We also

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  • Cited by (0)

    1

    These authors contributed equally to this work.

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    BD and AT are both senior authors.

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