PKCε Deficits in Alzheimer's Disease Brains and Skin Fibroblasts

In Alzheimer's disease (AD) transgenic mice, activation of synaptogenic protein kinase C epsilon (PKC epsilon) was found to prevent synaptotoxic amyloid-beta (A beta)-oligomer elevation, PKC epsilon deficits, early synaptic loss, cognitive deficits, and amyloid plaque formation. In humans, to study the role of PKC epsilon in the pathophysiology of AD and to evaluate its possible use as an early AD-biomarker, we examined PKC epsilon and A beta in the brains of autopsy-confirmed AD patients (n = 20) and age-matched controls (AC, n = 19), and in skin fibroblast samples from AD (n = 14), non-AD dementia patients (n = 14), and AC (n = 22). Intraneuronal A beta levels were measured immunohistochemically (using an A beta-specific antibody) in hippocampal pyramidal cells of human autopsy brains. PKC epsilon was significantly lower in the hippocampus and temporal pole areas of AD brains, whereas A beta levels were significantly higher. The ratio of PKC epsilon to A beta in individual CA1 pyramidal cells was markedly lower in the autopsy AD brains versus controls. PKC epsilon was inversely correlated with A beta levels in controls, whereas in AD patients, PKC epsilon showed no significant correlation with A beta. In autopsy brains, PKC epsilon decreased as the Braak score increased. Skin fibroblast samples from AD patients also demonstrated a deficit in PKC epsilon compared to controls and an AD-specific change in the A beta-oligomer effects on PKC epsilon. Together, these data demonstrate that the relationship between A beta levels and PKC epsilon is markedly altered in AD patients' brains and skin fibroblasts, reflecting a loss of protective effect of PKC epsilon against toxic A beta accumulation. These changes of PKC epsilon levels in human skin fibroblasts may provide an accurate, non-invasive peripheral AD biomarker.