Linkage of atypical protein kinase C to Alzheimer disease

Abstract Alzheimer disease (AD) is thought to be caused by build-up of neurotoxic plaques containing Aβ peptides cleaved from amyloid precursor protein by β-secretase, compounded by increases in phospho-tau-containing neuronal “tangles.” Late-onset AD is commonly associated with insulin-resistant states, and our findings suggest that hyperinsulinemia therein hyperactivates brain Akt and atypical protein kinase C (aPKC), and thusly activated aPKC (rather than Akt) leads to β-secretase activation and excessive production of Aβ peptides and phospho-tau. Interestingly, others have reported that aPKC activity is also increased in nondiabetic AD, apparently by noninsulin factors. Fortunately, control of hyperinsulinemia in mouse models of obesity/diabetes, and chemical blockade, or partial knockout, or expressional inhibition of brain aPKC can prevent the activation of β-secretase and excessive production of Aβ peptides and phospho-tau that are provoked by insulin and other agents. Chemical inhibitors of aPKC that pass the blood–brain barrier may have potential to treat AD.