Active immunization against alpha-synuclein ameliorates the degenerative pathology and prevents demyelination in a model of multiple system atrophy

Mandler, Markus; Valera, Elvira; Rockenstein, Edward; Mante, Michael; Weninger, Harald; Patrick, Christina; Adame, Anthony; Schmidhuber, Sabine; Santic, Radmila; Schneeberger, Achim; Schmidt, W.; Mattner, Frank; Masliah, Eliezer

doi:10.1186/s13024-015-0008-9

Cited by 136 publications

(134 citation statements)

References 55 publications

(88 reference statements)

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“…Moreover, when administered to a transgenic model of MSA, AFF 1 also induced a reduction in neurodegeneration and demyelination in neocortex, striatum, and corpus callosum [65]. The clearance of α-syn induced by AFF 1 involved activation of microglia, increased anti-inflammatory cytokine production, and reduced spreading of α-syn to astroglial cells [65,66]. These studies suggested that vaccination with AFFITOPEs could help ameliorate the neurodegenerative pathology in synucleinopathies.…”

Section: Immunotherapy Targeting Aβmentioning

confidence: 91%

“…These results suggested that α-syn vaccination is effective in reducing neuronal accumulation of α-syn aggregates and that further development of this approach might have a potential role in the treatment of synucleinopathies. Other active immunization approaches using AFFITOPEs (AFFiRiS AG) that mimic abnormal conformations of α-syn have been studied in animals model of PD and MSA [65,66]. AFFITOPEs that mimic the C-terminus region of α-syn are able to elicit an immune response specific to α-syn oligomers [66].…”

Section: Immunotherapy Targeting Aβmentioning

confidence: 99%

“…Vaccination with one of these AFFITOPEs (AFF 1) resulted in high antibody titers against α-syn aggregates, decreased accumulation of α-syn oligomers, reduced degeneration of tyrosine hydroxylase fibers in the caudoputamen nucleus, and improved motor and memory deficits in 2 α-syn transgenic models [66]. Moreover, when administered to a transgenic model of MSA, AFF 1 also induced a reduction in neurodegeneration and demyelination in neocortex, striatum, and corpus callosum [65]. The clearance of α-syn induced by AFF 1 involved activation of microglia, increased anti-inflammatory cytokine production, and reduced spreading of α-syn to astroglial cells [65,66].…”

Section: Immunotherapy Targeting Aβmentioning

confidence: 99%

“…Moreover, antibodies against these proteins can regulate inflammation and facilitate the clearance of target proteins via autophagy or microglia (Fig. 2) [61][62][63][64][65][66]. Neurodegenerative diseases are associated with signs of chronic neuroinflammation and elevated levels of several Fig.…”

Section: Introductionmentioning

confidence: 99%

“…Microgliosis, astrogliosis, and peripheral immune infiltration contribute to the cognitive and motor deficits, and lead to a toxic increase in the levels of reactive oxygen species [68], and to secondary neurodegeneration, characteristic of late disease stages [69]. Immunotherapy has been shown to induce a physiological microglial response (M2 type) and reduce the production of proinflammatory cytokines [65,66], thus exerting an anti-inflammatory effect in neurodegenerative disorders [70,71]. However, among the disadvantages of immunotherapy are the potential for autoimmune responses, nonspecific inflammatory reactions such as perivascular edema, need for repetitive administration, lack of response due to senescence of the innate immune system, and limited penetration of antibodies into the central nervous system.…”

Section: Introductionmentioning

confidence: 99%

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

2016

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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.

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Section: Immunotherapy Targeting Aβmentioning

confidence: 91%

Section: Immunotherapy Targeting Aβmentioning

confidence: 99%

Section: Immunotherapy Targeting Aβmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

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

2016

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α‐synuclein conformational antibodies fused to penetratin are effective in models of Lewy body disease

Spencer

Williams

Rockenstein

et al. 2016

Ann Clin Transl Neurol

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ObjectiveProgressive accumulation of α‐synuclein (α‐syn) has been associated with Parkinson's disease (PD) and Dementia with Lewy body (DLB). The mechanisms through which α‐syn leads to neurodegeneration are not completely clear; however, the formation of various oligomeric species have been proposed to play a role. Antibody therapy has shown effectiveness at reducing α‐syn accumulation in the central nervous system (CNS); however, most of these studies have been conducted utilizing antibodies that recognize both monomeric and higher molecular weight α‐syn. In this context, the main objective of this study was to investigate the efficacy of immunotherapy with single‐chain antibodies (scFVs) against specific conformational forms of α‐syn fused to a novel brain penetrating sequence.MethodWe screened various scFVs against α‐syn expressed from lentiviral vectors by intracerebral injections in an α‐syn tg model. The most effective scFVs were fused to the cell‐penetrating peptide penetratin to enhance transport across the blood–brain barrier, and lentiviral vectors were constructed and tested for efficacy following systemic delivery intraperitoneal into α‐syn tg mice.ResultTwo scFVs (D5 and 10H) selectively targeted different α‐syn oligomers and reduced the accumulation of α‐syn and ameliorated functional deficits when delivered late in disease development; however, only one of the antibodies (D5) was also effective when delivered early in disease development. These scFVs were also utilized in an enzyme‐linked immunosorbent assay (ELISA) assay to monitor the effects of immunotherapy on α‐syn oligomers in brain and plasma.InterpretationThe design and targeting of antibodies for specific species of α‐syn oligomers is crucial for therapeutic immunotherapy and might be of relevance for the treatment of Lewy body disease.

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Rational design of structure‐based vaccines targeting misfolded alpha‐synuclein conformers of Parkinson's disease and related disorders

Flores‐Fernandez,

Pesch,

Sriraman

et al. 2024

Bioengineering & Transla Med

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Synucleinopathies, including Parkinson's disease (PD), multiple system atrophy (MSA), and dementia with Lewy bodies (DLB), are neurodegenerative disorders caused by the accumulation of misfolded alpha‐synuclein protein. Developing effective vaccines against synucleinopathies is challenging due to the difficulty of stimulating an immune‐specific response against alpha‐synuclein without causing harmful autoimmune reactions, selectively targeting only pathological forms of alpha‐synuclein. Previous attempts using linear peptides and epitopes without control of the antigen structure failed in clinical trials. The immune system was unable to distinguish between native alpha‐synuclein and its amyloid form. The prion domain of the fungal HET‐s protein was selected as a scaffold to introduce select epitopes from the surface of alpha‐synuclein fibrils. Four vaccine candidates were generated by introducing specific amino acid substitutions onto the surface of the scaffold protein. The approach successfully mimicked the stacking of the parallel in‐register beta‐sheet structure seen in alpha‐synuclein fibrils. All vaccine candidates induced substantial levels of IgG antibodies that recognized pathological alpha‐synuclein fibrils derived from a synucleinopathy mouse model. Furthermore, the antisera recognized pathological alpha‐synuclein aggregates in brain lysates from patients who died from DLB, MSA, or PD, but did not recognize linear alpha‐synuclein peptides. Our approach, based on the rational design of vaccines using the structure of alpha‐synuclein amyloid fibrils and strict control over the exposed antigen structure used for immunization, as well as the ability to mimic aggregated alpha‐synuclein, provides a promising avenue toward developing effective vaccines against alpha‐synuclein fibrils.

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Active immunization against alpha-synuclein ameliorates the degenerative pathology and prevents demyelination in a model of multiple system atrophy

Cited by 136 publications

References 55 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

α‐synuclein conformational antibodies fused to penetratin are effective in models of Lewy body disease

Rational design of structure‐based vaccines targeting misfolded alpha‐synuclein conformers of Parkinson's disease and related disorders

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