Antibody-Aided Clearance of Extracellular α-Synuclein Prevents Cell-to-Cell Aggregate Transmission

Bae, Eun Jin; Lee, He Jin; Rockenstein, Edward; Ho, Dong Hwan; Park, Eun Bi; Yang, Na; Desplats, Paula; Masliah, Eliezer; Lee, Seung-Jae

doi:10.1523/jneurosci.1292-12.2012

Cited by 312 publications

(313 citation statements)

References 71 publications

Supporting

Mentioning

291

Contrasting

Unclassified

Order By: Relevance

“…Different groups have investigated which region of the α-syn protein is the best target for the development of disease-modifying monoclonal antibodies. We and others have observed that antibodies that recognize an epitope in the C-terminus of α-syn are more effective at ameliorating the pathology in transgenic mouse models of PD, as they clear intracellular aggregates, inhibit α-syn propagation, and prevent C-terminus cleavage of the protein, which may lead to increased aggregation [54,84,120,121]. However, other groups have reported that antibodies against the N-terminus are also effective at clearing α-syn aggregates, reducing their propagation, and diminishing motor dysfunctions [122,123].…”

Section: Immunotherapy Targeting Aβmentioning

confidence: 99%

See 1 more Smart Citation

Immunotherapeutic Approaches Targeting Amyloid-β, α-Synuclein, and Tau for the Treatment of Neurodegenerative Disorders

2016

View full text Add to dashboard Cite

Disease-modifying alternatives are sorely needed for the treatment of neurodegenerative disorders, a group of diseases that afflict approximately 50 million Americans annually. Immunotherapy is one of the most developed approaches in this direction. Vaccination against amyloid-β, α-synuclein, or tau has been extensively explored, specially as the discovery that these proteins may propagate cell-to-cell and be accessible to antibodies when embedded into the plasma membrane or in the extracellular space. Likewise, the use of passive immunization approaches with specific antibodies against abnormal conformations of these proteins has also yielded promising results. The clinical development of immunotherapies for Alzheimer's disease, Parkinson's disease, frontotemporal dementia, dementia with Lewy bodies, and other neurodegenerative disorders is a field in constant evolution. Results to date suggest that immunotherapy is a promising therapeutic approach for neurodegenerative diseases that progress with the accumulation and prion-like propagation of toxic protein aggregates. Here we provide an overview of the most novel and relevant immunotherapeutic advances targeting amyloid-β in Alzheimer's disease, α-synuclein in Alzheimer's disease and Parkinson's disease, and tau in Alzheimer's disease and frontotemporal dementia.

show abstract

Section: Immunotherapy Targeting Aβmentioning

confidence: 99%

“…Furthermore, antibodies may also prevent cell-to-cell propagation of α-syn and facilitate the clearance of extracellular α-syn [84,121,122] (Fig. 2) .…”

Section: Immunotherapy Targeting Aβmentioning

confidence: 99%

Immunotherapeutic Approaches Targeting Amyloid-β, α-Synuclein, and Tau for the Treatment of Neurodegenerative Disorders

2016

View full text Add to dashboard Cite

show abstract

“…It is unknown whether cell type-specific mechanisms exist or whether common mechanisms apply. For example, although there is some evidence that an antibody can block Tau aggregate uptake into HEK293 cells (84), other studies indicate that an anti-synuclein antibody can promote ␣-synuclein uptake into microglial cells in culture (85). Thus, it will be important to dissect the biology of cellular internalization and the role of antibodies so as to promote targeting of aggregates toward clearance pathways (e.g.…”

Section: Understanding Cell Uptakementioning

confidence: 99%

Prion-like Properties of Tau Protein: The Importance of Extracellular Tau as a Therapeutic Target

Holmes

Diamond

2014

Journal of Biological Chemistry

175

133

View full text Add to dashboard Cite

Work over the past 4 years indicates that multiple proteins associated with neurodegenerative diseases, especially Tau and ␣-synuclein, can propagate aggregates between cells in a prionlike manner. This means that once an aggregate is formed it can escape the cell of origin, contact a connected cell, enter the cell, and induce further aggregation via templated conformational change. The prion model predicts a key role for extracellular protein aggregates in mediating progression of disease. This suggests new therapeutic approaches based on blocking neuronal uptake of protein aggregates and promoting their clearance. This will likely include therapeutic antibodies or small molecules, both of which can be developed and optimized in vitro prior to preclinical studies.Neurodegenerative diseases account for an enormous human and financial cost to our society, estimated in excess of $200 billion annually (1). Despite decades of study, there is no disease-modifying therapy. Virtually all neurodegenerative diseases are associated with the accumulation of fibrillar protein aggregates, and all are relentlessly progressive. There is now abundant evidence for an association of neuronal networks with patterns of spread through the brain (2-4). Studies of relatively rare, dominantly inherited neurodegenerative diseases have indicated that proteins that accumulate in sporadic forms of disease, such as prion protein, Tau, ␣-synuclein, and TDP-43, also cause pathology in the setting of destabilizing point mutations (5-8). This provides a strong indication that protein aggregation is itself a proximal cause of disease and is not simply an epiphenomenon. Indeed, protein aggregation is the most unifying pathological feature of adult onset neurodegenerative disorders. The proximal initiators of protein aggregation likely vary among different proteins and cell types, whereas the accumulation of misfolded species in general appears to be linked to the age-dependent breakdown of cellular quality control pathways (9, 10). It is not understood, however, why neurodegenerative diseases are relentlessly progressive or why they involve neural networks (3,11,12). A variety of studies are consistent with the idea that mechanisms similar to those of propagation of prion pathology could underlie disease progression. Prion protein (PrP c ) 2 is a normal cellular protein that can be converted to a disease-causing conformation (PrP Sc ) through interaction with a pathogenic prion protein "seed." The conversion mechanism is not fully understood, but involves templated conformational change, whereby a PrP Sc seed contacts natively folded protein and induces it to assemble onto a growing aggregate. PrP Sc aggregates can have multiple conformations, each linked to unique pathological patterns (13-15), and they have been demonstrated in experimental systems to propagate through neural networks (16). Thus, the prion hypothesis provides a useful model by which to test ideas about propagation of protein pathology in other neurodegenerative diseases. Prion-...

show abstract

“…In this work, antibodies against α-synuclein allowed more rapid clearance of these aggregates through Fc receptors on microglia. Antibody-bound aggregates traffic more readily to the lysosomes of microglia, allowing for more effective breakdown and decreased cell-cell transfer of α-synuclein in a transgenic mouse model [109]. Both active and passive immunization against α-synuclein in a transgenic mouse model of PD decreased α-synuclein accumulation and decreased neurodegeneration and functional decline [110,111].…”

Section: Extracellular Clearance Degradation and Prevention Of Uptamentioning

confidence: 99%

Prion-Like Propagation of Protein Aggregation and Related Therapeutic Strategies

Kaufman

Diamond

2013

Neurotherapeutics

View full text Add to dashboard Cite

show abstract

Antibody-Aided Clearance of Extracellular α-Synuclein Prevents Cell-to-Cell Aggregate Transmission

Cited by 312 publications

References 71 publications

Immunotherapeutic Approaches Targeting Amyloid-β, α-Synuclein, and Tau for the Treatment of Neurodegenerative Disorders

Immunotherapeutic Approaches Targeting Amyloid-β, α-Synuclein, and Tau for the Treatment of Neurodegenerative Disorders

Prion-like Properties of Tau Protein: The Importance of Extracellular Tau as a Therapeutic Target

Prion-Like Propagation of Protein Aggregation and Related Therapeutic Strategies

Contact Info

Product

Resources

About