Fight Aging!

Just a few of the thousands of proteins in the human body can become altered and misfold in ways that encourage other molecules of that protein to do the same, forming aggregates that precipitate into toxic, solid deposits in cells and tissue. Neurodegenerative conditions in particular are characterized by these proteins, such as amyloid-β, TDP-43, tau, and α-synuclein, the last of which is the subject of today's open access paper. Parkinson's disease is the most studied of synucleinopathies, in which an excessive buildup of α-synuclein correlates with pathology and loss of function in the brain.

The common neurodegenerative conditions are associated with chronic, unresolved inflammation in brain tissue, and there is good reason to believe that this inflammation, disruptive of cell and tissue function, is an important part of the onset and progression of neurodegeneration. To what degree are the protein aggregates found in every aged brain, and in excessive amounts in patients with neurodegenerative conditions, involved in creating that inflammation? Are their contributions sizable in comparison to, say, the presence of persistent pathogens such as herpesviruses, or the growing burden of senescent supporting cells in the brain?

The Role of Alpha-Synuclein Autoantibodies in the Induction of Brain Inflammation and Neurodegeneration in Aged Humans

Aging is a major risk factor for developing neuroinflammation. As it progresses, neuroinflammation can cause neuron death in the brain, particularly in the hippocampus. This brain region is crucial for learning and memory function. Hence, aged humans who experience loss of neurons in this region exhibit frequent tendency of memory loss. Aging and its association for the development of numerous brain diseases are continuously increasing in prevalence. Increased plasma, cerebrospinal fluid (CSF), and brain level of alpha-synuclein (α-syn) and their association to microglial cells activation, pro-inflammatory cytokines production, neurodegeneration, and cognitive deficits have been observed in aged humans. However, the exact mechanism by which such α-syn abnormalities trigger neuroinflammation in aged humans are poorly defined.

Studies have shown that irregular accumulations and distributions of α-syn and/or the development of α-syn-reactive immunoglobulin G (IgG) autoantibodies are linked to the brain production of pro-inflammatory cytokines, i.e., interleukin-1 beta (IL1β), IL-6, and tumor necrosis factor alpha (TNF-α), which lead to neuron death and memory deficits in several age-related neurodegenerative diseases, i.e., Alzheimer's disease (AD), Parkinson's disease (PD), multiple system atrophy (MSA), rapid eye movement sleep behavior disorder (RBD), frontotemporal lobar dementia (PLD), and dementia with Lewy bodies (LBD). Therefore, this current study explored the involvement of α-syn, α-syn-reactive IgG autoantibodies, and Fc gamma receptors (FcγRs) function in aging human nervous system.

Based on the elevated brain expression of α-syn-reactive IgG auto antibodies and the higher expression of activating FcγR in aged humans, this report suggests that the α-syn-reactive IgG auto antibodies and their immunological reaction to α-syn are the basis of the formation of alpha-synuclein-specific IgG immune complexes (α-syn-IgG-ICs) in aged human brains. Furthermore, the strong interaction between such α-syn-IgG-ICs and activation of FcγR fuels the downstream signaling that causes microglial cells and/or neurons activation, pro-inflammatory cytokines production, and the death of neurons in aged humans.