The protein α-synuclein, like amyloid-β and tau, forms into an increasing amount of solid aggregates in the aging brain. These aggregates and their surrounding biochemistry cause neural dysfunction and cell death. Every older individual has raised levels of these protein aggregates, and the pathology they cause rises to the level of named condition when one or another is present in great enough amounts. The age-related diseases associated with α-synuclein are termed synucleinopathies, though one can argue that all neurodegeneration is to some degree influenced by all protein aggregates. Where the research, medical, and regulatory communities choose to draw the line between "normal" and "pathological" is somewhat arbitrary. If methods of reliably removing protein aggregates existed, every older individual should undergo treatment on a periodic basis, not just people with notably high levels of aggregates.
Parkinson's disease is the best known of the synucleinopathies, alongside dementia with Lewy bodies, and a few other less common conditions. Arguably α-synuclein is a meaningful cause of pathology in Alzheimer's patients as well. It might be better to think of the named conditions as rough, shifting territories outlined on a broad map of brain aging that combines differing levels of protein aggregation, vascular dysfunction, mitochondrial aging, immune system failure, and other causative processes. They are shorthand descriptions for large and varied chunks of a complicated landscape.
In today's open access paper, researchers present evidence for inhibition of TLR2 as a potential strategy to dampen the progression of synucleinopathy. TLR2 is a part of mechanisms that trigger the immune system into action, and in this case the activities of glial cells of the brain are the focus point. Glial cells are known to become dysregulated and inflammatory in the aging brain, and suppressing that inappropriate behavior is one possible path towards a slowing of progression towards pathology. Therapies of this nature don't directly address the underlying damage that causes immune dysfunction, but any effort that at least somewhat sets the immune system back on track may result in increased repair and maintenance by immune cells. The size of the effect is very much dependent on the details of the case at hand, of course.
Following Alzheimer's Disease (AD), synucleinopathies such as Parkinson's disease (PD) and dementia with Lewy bodies (DLB) are the second most common group of neurodegenerative disorders of the aging population. Overall, they represent heterogeneous group of neurological conditions, characterized by progressive accumulation of α-synuclein in neuronal and glial cells. The mechanisms through which the various species of α-synuclein aggregates lead to selective neurodegeneration and neuroinflammation is not completely understood. Transmission of α-synuclein aggregates from neuron-to-neuron and neuron-to-glia has been suggested as the underlying mechanism of the neurodegeneration and neuroinflammation in synucleinopathy.
We have previously shown that the oligomeric forms of extracellular α-synuclein interact with Toll-like receptor 2 (TLR2) on the surface of neurons and glial cells. This results in neuro-inflammatory responses with TNFα and IL-6 production. TLR2 belongs to a family of pattern recognition receptor which modulate responses to exogenous pathogens as well as endogenous misfolded proteins released following damage and cellular stress. In the central nervous system, TLR2 is expressed in glial cells and neuronal populations, and recent studies have shown that the levels of TLR2 are elevated in neurodegenerative disorders such as AD and PD.
We have recently shown that inhibition of TLR2 by gene deletion or siRNA-mediated knock down rescues the pathology associated with α-synuclein accumulation in cellular models and transgenic mice. Therefore, TLR2 and downstream signaling have been suggested a new therapeutic target for synucleinopathy. Neutralizing TLR2 with a monoclonal antibody has been recently shown to ameliorate the pathology in a murine model of AD.
The main objective of this study was to evaluate the therapeutic effects of targeting TLR2 with a functional inhibitory antibody (anti-TLR2). We show that the administration of anti-TLR2 was able to decrease the accumulation of neuronal and astroglial α-synuclein, resulting in reduced neuroinflammation, neurodegeneration, and behavioral deficits in an α-synuclein transgenic mouse model of PD/DLB. Moreover, the anti-TLR2 blocked neuron-to-neuron and neuron-to-astrocyte α-synuclein transmission and reduced pro-inflammatory responses in a cell based model. Therefore, TLR2 might be a viable target and TLR2 immunotherapy is a novel therapeutic strategy for synucleinopathies of the aging population.