Passive anti-amyloid immunotherapy in Alzheimer's disease: What are the most promising targets?

Moreth, Jens; Mavoungou, Chrystelle; Schindowski, Katharina

doi:10.1186/1742-4933-10-18

Cited by 97 publications

(75 citation statements)

References 71 publications

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“…In this sense, the use of antibodies directed against specific epitopes or conformations of Aβ has yielded promising results. Passive immunization approaches using monoclonal antibodies against Aβ1-40 [103], Aβ1-42 [104], pyroglutamate Aβ [105], oligomers [106], or protofibrils [107][108][109] have been developed. Currently, clinical trials with the antibodies BAN2401 (recognizing protofibrils) [75], crenezumab (aggregated species) [76], gantenerumab (fibrils) [78][79][80], and solanezumab (Aβ mid-domain) [81,82] are ongoing (Table 1).…”

Section: Immunotherapy Targeting Aβmentioning

confidence: 99%

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: 99%

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

2016

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“…Efficient treatment strategies are still limited and an aging society in demographic change presents an enormous challenge to the health systems of industrialized nations. Despite the extensive research and effort to uncover the mechanism of AD pathogenesis, more or less all drug candidates failed to demonstrate significant effects on cognition in clinical trials [3,4].…”

Section: Cns Delivery -An Unmet Medical Needmentioning

confidence: 99%

“…Currently, all biopharmaceuticals that are used or being evaluated in the clinics for CNS disease act predominantly via peripheral mechanism: e.g. anti-amyloid- (A) capturing monoclonal/polyclonal antibodies in AD [3,4] or immune cell regulating biopharmaceuticals in multiple sclerosis [11]. However, candidate biopharmaceuticals reveal promising results in cellular models or in animal models when delivered intracerebroventricular.…”

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confidence: 99%

Nose-to-Brain delivery of insulin for Alzheimer’s disease

Stützle¹,

Flamm²,

Carle

et al. 2015

ADMET DMPK

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The transport of small molecules, peptides and proteins via the olfactory epithelium and along olfactory and trigeminal nerve pathways from the nasal cavity to the brain is very well known and clinically established for central nervous system (CNS) active drugs like oxytocin, sumatriptan or insulin. Insulin is a clinically well-established biopharmaceutical with a validated function in cognition. Central supply with insulin via intranasal administration improves cognition in animal models CNS delivery -an unmet medical needThe World Health Organization (WHO) estimates that more than a billion people worldwide are suffering from diseases of the central nervous system (CNS; [1,2]). Alzheimer's disease (AD) is the most common neurodegenerative dementia in the industrialized world, with prevalence rates well over 30 % in the over 80-years-old population [1,2]. AD causes enormous costs to the social healthcare systems, as well as personal tragedies for the patients, families and caregivers. Like most neurodegenerative diseases, AD has a poor prognosis and only symptomatic therapy is currently available. Efficient treatment strategies are still limited and an aging society in demographic change presents an enormous challenge to the health systems of industrialized nations. Despite the extensive research and effort to uncover the mechanism of AD pathogenesis, more or less all drug candidates failed to demonstrate significant effects on cognition in clinical trials [3,4].A highly critical point in that context is the low central availability of drugs. The passage of most CNSactive drugs and in particular of biopharmaceuticals is massively hampered by the blood-brain barrier

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“…However, recent clinical trials with these therapies showed no benefit, and, in some cases, caused harm 12 . An unexploited strategy to modulate Aβ production is to alter the sub-cellular localization of APP and γ-secretase interaction.…”

Section: Introductionmentioning

confidence: 99%

Imaging the Intracellular Trafficking of APP with Photoactivatable GFP

Tam¹,

Pasternak

2015

JoVE

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Beta-amyloid (Aβ) is the major constituent of senile plaques found in the brains of Alzheimer's disease patients. Aβ is derived from the sequential cleavage of Amyloid Precursor Protein (APP) by β and γ-secretases. Despite the importance of Aβ to AD pathology, the subcellular localization of these cleavages is not well established. Work in our laboratory and others implicate the endosomal/lysosomal system in APP processing after internalization from the cell surface. However, the intracellular trafficking of APP is relatively understudied.While cell-surface proteins are amendable to many labeling techniques, there are no simple methods for following the trafficking of membrane proteins from the Golgi. To this end, we created APP constructs that were tagged with photo-activatable GFP (paGFP) at the C-terminus. After synthesis, paGFP has low basal fluorescence, but it can be stimulated with 413 nm light to produce a strong, stable green fluorescence. By using the Golgi marker Galactosyl transferase coupled to Cyan Fluorescent Protein (GalT-CFP) as a target, we are able to accurately photoactivate APP in the trans-Golgi network. Photo-activated APP-paGFP can then be followed as it traffics to downstream compartments identified with fluorescently tagged compartment marker proteins for the early endosome (Rab5), the late endosome (Rab9) and the lysosome (LAMP1). Furthermore, using inhibitors to APP processing including chloroquine or the γ-secretase inhibitor L685, 458, we are able to perform pulse-chase experiments to examine the processing of APP in single cells.We find that a large fraction of APP moves rapidly to the lysosome without appearing at the cell surface, and is then cleared from the lysosome by secretase-like cleavages. This technique demonstrates the utility of paGFP for following the trafficking and processing of intracellular proteins from the Golgi to downstream compartments. Video LinkThe video component of this article can be found at

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Passive anti-amyloid immunotherapy in Alzheimer's disease: What are the most promising targets?

Cited by 97 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

Nose-to-Brain delivery of insulin for Alzheimer’s disease

Imaging the Intracellular Trafficking of APP with Photoactivatable GFP

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