Abstract
BackgroundThe lack of effective treatment options for Alzheimer’s disease (AD) is of momentous societal concern. Synaptic loss is the hallmark of AD that correlates best with impaired memory and occurs early in the disease process, before the onset of clinical symptoms. We have developed a small-molecule, pyridazine-based series that enhances the structure and function of both the glial processes and the synaptic boutons that form the tripartite synapse. Previously, we have shown that these pyridazine derivatives exhibit profound efficacy in an amyloid precursor protein AD model. Here, we evaluated the efficacy of an advanced compound, LDN/OSU-0215111, in rTg4510 mice—an aggressive tauopathy model.MethodsrTg4510 mice were treated orally with vehicle or LDN/OSU-0215111 (10 mg/kg) daily from the early symptomatic stage (2 months old) to moderate (4 months old) and severe (8 months old) disease stages. At each time point, mice were subjected to a battery of behavioral tests to assess the activity levels and cognition. Also, tissue collections were performed on a subset of mice to analyze the tripartite synaptic changes, neurodegeneration, gliosis, and tau phosphorylation as assessed by immunohistochemistry and Western blotting. At 8 months of age, a subset of rTg4510 mice treated with compound was switched to vehicle treatment and analyzed behaviorally and biochemically 30 days after treatment cessation.ResultsAt both the moderate and severe disease stages, compound treatment normalized cognition and behavior as well as reduced synaptic loss, neurodegeneration, tau hyperphosporylation, and neuroinflammation. Importantly, after 30 days of treatment cessation, the benefits of compound treatment were sustained, indicating disease modification. We also found that compound treatment rapidly and robustly reduced tau hyperphosphorylation/deposition possibly via the inhibition of GSK3β.ConclusionsThe results show that LDN/OSU-0215111 provides benefits for multiple aspects of tauopathy-dependent pathology found in Alzheimer’s disease including tripartite synapse normalization and reduction of toxic tau burden, which, in turn, likely accounted for normalized cognition and activity levels in compound-treated rTg4510 mice. This study, in combination with our previous work regarding the benefit of pyridazine derivatives against amyloid-dependent pathology, strongly supports pyridazine derivatives as a viable, clinically relevant, and disease-modifying treatment for many of the facets of Alzheimer’s disease.
Highlights
The lack of effective treatment options for Alzheimer’s disease (AD) is of momentous societal concern
We found that compound treatment directly reduced toxic forms of mutant phosphorylated tau and deposition through inhibition of the tau kinase glycogen synthase kinase-3 beta (GSK3β)
In the novel object recognition test (NORT), rTg4510 mice again selected between a novel and familiar object at random while rTg4510 × Excitatory amino acid transporter 2 (EAAT2) mice preferentially interacted with the novel object like the control groups (Fig. 1b)
Summary
The lack of effective treatment options for Alzheimer’s disease (AD) is of momentous societal concern. Synaptic loss is the hallmark of AD that correlates best with impaired memory and occurs early in the disease process, before the onset of clinical symptoms. Alzheimer’s disease (AD) is a devastating, progressive neurodegenerative disease that affects approximately 50 million people worldwide and still lacks effective therapeutic options [1, 2]. Therapeutic approaches have been developed to enhance brain clearance of accumulated amyloid β and aberrant tau aggregation [9,10,11,12,13]; these approaches have not yet demonstrated success in humans. Studies in AD brains indicate that cognitive deficits are more highly correlated with loss of glutamatergic synapses than with neurofibrillary tangles or amyloid β burden [16,17,18]. Preventing excess glutamate-mediated toxicity and hyperexcitability is a potential therapeutic target
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
