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Olfactory dysfunction is a recognized risk factor for the pathogenesis of Alzheimer’s disease (AD), while the mechanisms are still not clear. Here, we applied bilateral olfactory bulbectomy (OBX), an olfactory deprivation surgery to cause permanent anosmia, in human tau-overexpressed mice (htau mice) to investigate changes of AD-like pathologies including aggregation of abnormally phosphorylated tau and cholinergic neuron loss. We found that tau phosphorylation in hippocampus was increased at Thr-205, Ser-214, Thr-231, and Ser-396 after OBX. OBX also increased the level of sarkosyl-insoluble Tau at those epitopes and accelerated accumulation of somatodendritic tau. Moreover, OBX resulted in the elevation of calpain activity accompanied by an increased expression of the cyclin-dependent kinase 5 (cdk5) neuronal activators, p35 and p25, in hippocampus. Furthermore, OBX induces the loss of the cholinergic neurons in medial septal. Administration of cdk5 pharmacological inhibitor roscovitine into lateral ventricles suppressed tau hyperphosphorylation and mislocalization and restored the cholinergic neuron loss. These findings suggest that olfactory deprivation by OBX hastens tau pathology and cholinergic system impairment in htau mice possibly via activation of cdk5.

Protein kinase A (PKA) plays a crucial role in tau hyperphosphorylation, an early event of Alzheimer disease (AD), and 17β-estradiol replacement in aging women forestalls the onset of AD. However, the role of estradiol in PKA-induced tau hyperphosphorylation is not known. Here, we investigated the effect of 17β-estradiol on cAMP/PKA activity and the PKA-induced tau hyperphosphorylation in HEK293 cells stably expressing tau441. We found that 17β-estradiol effectively attenuated forskolin-induced overactivation of PKA and elevation of cAMP, and thus prevented tau from hyperphosphorylation. These data provide the first evidence that 17β-estradiol can inhibit PKA overactivation and the PKA-induced tau hyperphosphorylation, implying a preventive role of 17β-estradiol in AD-like tau pathology.