Immunotherapies for Aging-Related Neurodegenerative Diseases—Emerging Perspectives and New Targets

Abstract

Neurological disorders such as Alzheimer's disease (AD), Lewy body dementia (LBD), frontotemporal dementia (FTD), and vascular dementia (VCID) have no disease-modifying treatments to date and now constitute a dementia crisis that affects 5 million in the USA and over 50 million worldwide. The most common pathological hallmark of these age-related neurodegenerative diseases is the accumulation of specific proteins, including amyloid beta (Aβ), tau, α-synuclein (α-syn), TAR DNAbinding protein 43 (TDP43), and repeat-associated non-ATG (RAN) peptides, in the intra-and extracellular spaces of selected brain regions. Whereas it remains controversial whether these accumulations are pathogenic or merely a byproduct of disease, the majority of therapeutic research has focused on clearing protein aggregates. Immunotherapies have garnered particular attention for their ability to target specific protein strains and conformations as well as promote clearance. Immunotherapies can also be neuroprotective: by neutralizing extracellular protein aggregates, they reduce spread, synaptic damage, and neuroinflammation. This review will briefly examine the current state of research in immunotherapies against the 3 most commonly targeted proteins for age-related neurodegenerative disease: Aβ, tau, and α-syn. The discussion will then turn to combinatorial strategies that enhance the effects of immunotherapy against aggregating protein, followed by new potential targets of immunotherapy such as aging-related processes.

Monoclonal Antibodies as Neurological Therapeutics

“…Recent experimental data suggest that PD progression may arise due to spreading of pathological forms of extracellular α-synuclein throughout the brain via a cellular release, uptake and seeding mechanism. Cinpanemab, a recombinant humanized anti-α synuclein IgG1 mAb targeting aggregated α-synuclein is currently in Phase 2 trial (BIIB054) [ 120 ], which followed a single ascending dose phase 1 study [ 121 ].…”

Passive Immunization With a Novel Monoclonal Anti-PrP Antibody TW1 in an Alzheimer’s Mouse Model With Tau Pathology

“…There are no disease-modifying therapeutic interventions for AD (Long and Holtzman, 2019;Wisniewski and Drummond, 2019). However, immunotherapy is emerging as a promising therapy to treat AD (Kwon et al, 2020). Numerous studies of passive immunization with anti-amyloid (Aβ) antibodies have demonstrated effective clearance of amyloid Aβ together with cognitive improvements in transgenic animal models (Herline et al, 2018a;Kwon et al, 2020).…”

“…However, immunotherapy is emerging as a promising therapy to treat AD (Kwon et al, 2020). Numerous studies of passive immunization with anti-amyloid (Aβ) antibodies have demonstrated effective clearance of amyloid Aβ together with cognitive improvements in transgenic animal models (Herline et al, 2018a;Kwon et al, 2020). However, active and passive immunization targeting Aβ has failed in all clinical trials thus far, with the possible recent exception of aducanumab (Loureiro et al, 2020;Plotkin and Cashman, 2020), an antibody that is more specific to insoluble fibrillary and oligomeric forms of Aβ (Arndt et al, 2018;Tolar et al, 2020).…”

“…There is a growing realization that the most toxic species of Aβ are oligomeric (Viola and Klein, 2015); similarly, it is also thought that oligomeric species of other proteins (i.e., tau, α-synuclein, TDP-43, etc.) that accumulate in association with neurodegenerative diseases are the most neurotoxic (Kwon et al, 2020). Hence it has been proposed that the inhibition of oligomer mediated toxicity by immunotherapy is the most likely approach to be clinically successful, for AD and other neurodegenerative disorders (Wisniewski and Goñi, 2015;Herline et al, 2018a).…”

“…Hence it has been proposed that the inhibition of oligomer mediated toxicity by immunotherapy is the most likely approach to be clinically successful, for AD and other neurodegenerative disorders (Wisniewski and Goñi, 2015;Herline et al, 2018a). Tau targeted immunotherapies are currently also being developed; however, less effort has been directed on interventions targeting tau pathology compared to Aβ (Li and Götz, 2017;Götz and Götz, 2019;Kwon et al, 2020;Vaz and Silvestre, 2020). In the present study, we aimed to test a novel immunotherapeutic approach's ability to ameliorate tau-related pathology by blocking oligomer mediated toxicity, using an AD transgenic (Tg) model, which we developed (Boutajangout et al, 2008(Boutajangout et al, , 2009(Boutajangout et al, , 2010.…”