Solving neurodegeneration: common mechanisms and strategies for new treatments

Abstract

Across neurodegenerative diseases, common mechanisms may reveal novel therapeutic targets based on neuronal protection, repair, or regeneration, independent of etiology or site of disease pathology. To address these mechanisms and discuss emerging treatments, in April, 2021, Glaucoma Research Foundation, BrightFocus Foundation, and the Melza M. and Frank Theodore Barr Foundation collaborated to bring together key opinion leaders and experts in the field of neurodegenerative disease for a virtual meeting titled "Solving Neurodegeneration". This "think-tank" style meeting focused on uncovering common mechanistic roots of neurodegenerative disease and promising targets for new treatments, catalyzed by the goal of finding new treatments for glaucoma, the world's leading cause of irreversible blindness and the common interest of the three hosting foundations. Glaucoma, which causes vision loss through degeneration of the optic nerve, likely shares early cellular and molecular events with other neurodegenerative diseases of the central nervous system. Here we discuss major areas of mechanistic overlap between neurodegenerative diseases of the central nervous system: neuroinflammation, bioenergetics and metabolism, genetic contributions, and neurovascular interactions. We summarize important discussion points with emphasis on the research areas that are most innovative and promising in the treatment of neurodegeneration yet require further development. The research that is highlighted provides unique opportunities for collaboration that will lead to efforts in preventing neurodegeneration and ultimately vision loss.

Keywords: Alzheimer’s Disease; Biomarker; Cell-replacement; Detection; Genetics; Glaucoma; Glia; Huntington’s Disease; Imaging; Metabolic stress; Model Systems; Neuro-regeneration; Neuro-replacement; Neurodegeneration; Neurovascular coupling; Organoids; Parkinson’s Disease.

Fig. 1

Common mechanisms of neurodegeneration. Across neurodegenerative diseases, five main areas of mechanistic overlap exist, these include: (1) environmental factors such as diet, age, and, exercise; (2) metabolic stress, e.g., mitochondrial dysfunction, increased reactive oxygen species (ROS); (3) genetic contributions, e.g., genome-wide association study-linked risk alleles (GWAS), sex-linked genetic contributions; (4) neurovascular coupling, e.g., breakdown of the blood-brain-barrier and dysfunctional neurovascular coupling and; (5) neuroinflammation, e.g., infiltration of peripheral immune cells, and increased glial reactivity. Environmental factors contribute to all mechanistic areas of degeneration

Fig. 2

Biomarkers for neurodegenerative diseases. Numerous biomarkers for neurodegeneration are being developed. Amyloid pathology in AD can be readily detected in plasma by measuring the Aβ42/ Aβ40 ratio. Alternatively, larger Aβ plaques and fibrils can be detected visually by Aβ-PET. Similarly, tau pathology can be detected as p-tau in plasma and cerebrospinal fluid (CSF), and tau plaques can be identified as fibrils on PET. Lewy bodies, composed of misfolded α-synuclein (α-syn), can be detected in CSF of PD patients or by using α-syn seeding assays such as α-syn RT-QuIC. Neurofilament light protein (NfL), a marker of degenerating myelinated axons is detectable in CSF and plasma. Several novel emerging biomarkers include neurogranin, a marker of post-synaptic degeneration and synaptic vesicle 2 A (SV2A), a pre-synaptic marker of degeneration. In addition, the presence of reactive gial cell markers (e.g., glial acidic fibrillary protein; GFAP, monocyte chemoattractant protein-1; (MCP-1) and Triggering Receptor Expressed On Myeloid Cells 2; TREM2) in CSF and plasma are being explored as novel biomarkers in neurodegeneration

Fig. 3

Model systems for studying neurodegeneration. Established experimental models of disease can be categorized into three main areas: in vitro, ex vivo and in vivo. Each type of model system has advantages that can be leveraged to explore disease mechanisms; however, disadvantages exist for each avenue. In vitro models such as cell lines and purified primary cells are a rapid and inexpensive way to explore disease mechanisms, however, extrapolation of results to biological systems is difficult. Ex vivo models, such as the growth of organoids in culture or explanted tissue cultures are multicellular, allow more complex mechanistic questions to be explored. However, they are not ideal representations of in vivo situations due to lack of vascular or peripheral immune components. In vivo models include animals such as non-human primates, mice and rats, Drosophila and Caenorhabditis elegans, and others. Although these models allow for in vivo studies of disease, the cost is high, and the results may not always translate well to human biology.