Genome-wide association studies have identified strong associations between the 
risk of developing Parkinson's disease (PD) and polymorphisms in the genes 
encoding α-synuclein and the microtubule-associated protein tau. However, the 
contribution of tau and its phosphorylated form (p-tau) to α-synuclein-induced 
pathology and neuronal dysfunction remains controversial. We have assessed the 
effects of NAP (davunetide), an eight-amino acid peptide that decreases tau 
hyperphosphorylation, in mice overexpressing wild-type human α-synuclein 
(Thy1-aSyn mice), a model that recapitulates aspects of PD. We found that the 
p-tau/tau level increased in a subcortical tissue block that includes the 
striatum and brain stem, and in the cerebellum of the Thy1-aSyn mice compared to 
nontransgenic controls. Intermittent intranasal NAP administration at 2 μg/mouse 
per day, 5 days a week, for 24 weeks, starting at 4 weeks of age, significantly 
decreased the ratio of p-tau/tau levels in the subcortical region while a higher 
dose of 15 μg/mouse per day induced a decrease in p-tau/tau levels in the 
cerebellum. Both NAP doses reduced hyperactivity, improved habituation to a 
novel environment, and reduced olfactory deficits in the Thy1-aSyn mice, but 
neither dose improved the severe deficits of motor coordination observed on the 
challenging beam and pole, contrasting with previous data obtained with 
continuous daily administration of the drug. The data reveal novel effects of 
NAP on brain p-tau/tau and behavioral outcomes in this model of synucleinopathy 
and suggest that sustained exposure to NAP may be necessary for maximal 
benefits.