The three most harmful forms of metabolic waste in the aging brain are amyloid-β, hyperphosphorylated tau, and α-synuclein, all of which precipitate into solid deposits with a complex halo of surrounding biochemistry that damages and ultimately kills cells. They contribute to various age-related neurodegenerative conditions that are classified as amyloidosis, tauopathy, and synucleinopathy, respectively. Looking at just one of these forms of waste in isolation misses the real story, however. An aging brain has some of each, and it is apparent from the study of Alzheimer's disease that amyloid-β and tau interact to produce greater harm together than either does on its own. So should we be surprised to find evidence that tau and α-synuclein also have synergies in well known synucleinopathies such as Parkinson's disease? Perhaps not.
This sort of finding favors approaches to clearance of metabolic waste that tackle all of it at once, not just selective types. The most expensive, and so far failed, immunotherapies for Alzheimer's disease, for example, focus specifically on amyloid-β, or more recently specifically on tau. The more that we see interaction between these forms of damaged protein in the brain, the more we should favor methodologies for clearance of all waste present in cerebrospinal fluid, such as the Leucadia Therapeutics line of development, or various means of restoring the activity of microglial cells responsible for clearing out unwanted proteins and other debris.
Parkinson's disease (PD) and Lewy body dementia (LBD), behind Alzheimer's disease (AD), are the most common neurodegenerative disorders with no effective therapies targeting the cause of disease. The pathological hallmarks of PD are cytoplasmic inclusions called Lewy bodies (LB), comprised primarily of α-synuclein, along with hyperphosphorylated tau and other sequestered proteins, in dopaminergic neurons. However, the importance of LB to the neurotoxicity in disease has been questioned. A number of studies have shown that oligomeric α-synuclein is the toxic species, rather than fibrils comprising LBs, and that α-synuclein oligomers may be the most effective therapeutic target.
In spite of the clear prevalence of α-synuclein pathology in disease, one of the greatest genetic risk factors for PD is tau, the role of which is understudied and poorly understood. Phosphorylated tau aggregates have been reported in numerous synucleinopathy mouse models, suggesting a possible synergistic interaction between α-synuclein and tau in mediating neurodegeneration in PD, as α-synuclein may increase tau aggregation and tau may have a similar effect on α-synuclein. While neurofibrillary tangles (NFTs) characterize tauopathies and are not correlative of synucleinopathies, recent studies suggest that intermediate forms of tau - tau oligomers - that form prior to or independently of NFTs, are the true toxic species in disease and the optimum targets for anti-tau therapies.
We have evaluated the efficacy of targeting the toxic, oligomeric form of tau protein by passive immunotherapy in a mouse model of synucleinopathy. We treated seven-month-old mice overexpressing mutated α-synuclein (A53T mice) with tau oligomer-specific monoclonal antibody (TOMA) and a control antibody and assessed both behavioral and pathological phenotypes. We found that A53T mice treated with TOMA were protected from cognitive and motor deficits two weeks after a single injection. Levels of toxic tau oligomers were specifically decreased in the brains of TOMA-treated mice. Tau oligomer depletion also protected against dopamine and synaptic protein loss. These results indicate that targeting tau oligomers is beneficial for a mouse model of synucleinopathy and may be a viable therapeutic strategy for treating diseases in which tau and α-synuclein have a synergistic toxicity.