Hippocampal phosphorylated tau induced cognitive decline, dendritic spine loss and mitochondrial abnormalities in a mouse model of Alzheimer's disease

The purpose of our study was to understand the toxic effects of hippocampal phosphorylated tau in tau mice. Using rotarod and Morris water maze (MWM) tests, immunoblotting and immunofluorescence, Golgi-Cox staining and transmission electron microscopy, we assessed cognitive behavior,measured protein levels ofmitochondrial dynamics, MAP2, total and phosphorylated tau, and quantified dendritic spines andmitochondrial number and length in 12-month-old tau mice with P301L mutation. Mitochondrial function was assessed bymeasuring the levels of H₂O₂, lipid peroxidation, cytochrome oxidase activity andmitochondrial ATP. MWMand rotarod tests revealed that hippocampal learning andmemory and motor learning and coordination were impaired in taumice relative to wild-type (WT)mice. Increased levels ofmitochondrial fission proteins, Drp1 and Fis1 and decreased levels ofmitochondrial fusion proteins, Mfn1, Mfn2 and Opa1 were found in 12-month-old taumice relative to agematchedWTmice, indicating that the presence of abnormalmitochondrial dynamics in taumice. Decreased levels of dendritic protein, MAP2 and increased levels of total and phosphorylated tau proteins were found in taumice relative toWTmice. Mitochondrial function was defective. Golgi-Cox staining analysis revealed that dendritic spines are significantly reduced. Transmission electron microscopy revealed significantly increasedmitochondrial numbers and reducedmitochondrial length in taumice. These findings suggest that hippocampal accumulation of phosphorylated tau is responsible for abnormalmitochondrial dynamics and reducing dendritic proteinMAP2 and dendritic spines and hippocampal based learning and memory impairments, andmitochondrial structural and functional changes in taumice. Based on these observations, we propose that reduced hippocampal phosphorylated tau is an important therapeutic strategy for AD and other tauopathies.