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 DNA-binding 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.

Keywords: Alzheimer’s disease; Aβ; Immunotherapy; tau; vaccination; α-synuclein.

Fig. 1

Combined mechanisms of neurodegeneration in AD/ADRD include protein accumulation and aging-related pathways. In the neurodegenerative process of AD/ADRD, synaptic damage and neuroinflammation may lead to neuronal dysfunction which results in dementia and motor deficits. The leading hypothesis is that progressive accumulation of proteins such as amyloid beta (Aβ), tau, α-synuclein (α-syn), TAR DNA-binding protein 43 (TDP43), and repeat-associated non-ATG (RAN) is the primary culprit. However, aging is also likely to play a critical role in pathogenesis, either in synergy with protein accumulation or as an independent pathway. Aging processes relevant to neurodegeneration include inflammation, proteostasis, DNA damage, cell senescence, and mitochondrial alterations

Fig. 2

Overlapping protein aggregate pathology in AD/ADRD. Although Aβ and tau are classically associated with AD, α-syn with Lewy body dementia, and TDP43 and tau with FTD and limbic associated TDP43 encephalopathy (LATE), it is becoming increasingly evident that older individuals with dementia (+ 80 years old) display mixed pathology

Fig. 3

Mechanisms of protein toxicity in AD/ADRD involve oligomerization and propagation of protein aggregates. In neurodegeneration, an imbalance in the synthesis, aggregation, and clearance of proteins results in chronic accumulation, leading to further aggregation and propagation, and eventually inflammation and neurodegeneration

Fig. 4

Multiple mechanisms of action of immunotherapy in AD/ADRD. Immunotherapy involves various mechanisms of action to target protein aggregates in the membrane and the intra- and extracellular spaces. Antibodies can block propagation, trigger lysosomal clearance of proteins, reduce inflammation, and promote neuroprotection

Fig. 5

Combination immunotherapies for AD/ADRD targeting protein aggregates and aging-related pathways. Immunotherapy can also be used to target other pathogens and age-related pathogenic processes associated with aging. One such pathogen may be the herpes simplex virus (#1). Aging-related pathways that can be targeted with antibodies include inflammation (e.g., TNF, TLR2, inflammasome) (#2), senescent cells (e.g., DPP4) (#3), and immune surveillance cells (e.g., NK cells) (#4). Immunotherapies in neurodegeneration have been traditionally developed to target protein aggregates (e.g., Aβ, tau, α-syn, TDP43) (#5) alone or in combination (#6). Combination therapies may involve targeting multiple protein aggregates (#6) or protein aggregates (#5) and age-related pathways (#1–4)