Abstract
Background and Purpose: Cooperative defect is one of the earliest
manifestations of patients with Alzheimer’s disease (AD), but the
underlying mechanism remains unclear. The purpose of the current study
was to address this issue. Experimental Approach: The cooperative
function of APP/PS1 transgenic AD model mice at ages 2, 5 and 8 months
was evaluated by a cooperative drinking task. Neuropathological changes
were examined in the medial prefrontal cortex (mPFC), a key brain area
regulating social behavior. Another experiment was designed to observe
whether miconazole, a drug has a protective effect on myelin sheath,
could promote cooperative ability of APP/PS1 mice in the early AD-like
stage. The protective effects of miconazole on cultured mouse cortical
oligodendrocytes exposed to human amyloid β peptide (Aβ1-42) peptide
were also investigated. Key Results: There was an age-dependent
impairment of cooperative drinking water behavior in APP/PS1 mice. AD
mice with cooperative dysfunction showed decreases in myelin sheath
thickness, oligodendrocyte nuclear heterochromatin percentage and myelin
basic protein expression levels in the mPFC. The cooperative ability was
significantly improved in APP/PS1 mice treated with miconazole.
Consistently, miconazole increased oligodendrocyte maturation and myelin
sheath thickness, without reducing Aβ plaque deposition in the mPFC.
Miconazole protected cultured oligodendrocytes from the toxicity of
Aβ1-42. Conclusions and Implications: These results demonstrate that
mPFC myelin hypomyelination is involved in cooperative deficits of
APP/PS1 mice. Improving myelination via miconazole therapy may offer a
potential therapeutic approach for early intervention of AD.