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Alzheimer’s disease (AD) is commonly, not always, associated with insulin-resistant, hyperinsulinemic, and obesity/type-2-diabetic (O/T2D) states. Partial deficiencies of brain insulin receptor (IR) indeed occur in both O/T2D-AD and human AD, but these deficiencies can be bypassed by hyperinsulinemia, which activates atypical protein kinase C (aPKC) and β-secretase, increases Aβ-peptide and phospho-thr-231-tau levels, and induces memory impairments; importantly, these aberrations are reversed by reduction of liver/aPKC-dependent hyperinsulinemia or direct blockade of brain aPKC. New evidence shows that aPKC acts via nuclear factor kappa-B to increase β-secretase mRNA/protein levels in brain, where β-secretase acts on both β-amyloid precursor protein to increase AD risk and IR to limit beneficial (aPKC independent) insulin effects, particularly in normo/hypoinsulinemic AD, and liver, where β-secretase acts on IR to initiate or abet development of insulin resistance and compensatory hyperinsulinemia that originates from diet-induced hepatic aPKC activation. Fortunately, agents that inhibit PKC-λ/ι in brain, liver, or both effectively reduce β-secretase levels and adverse actions therein, and moreover, prevent/reverse O/T2D and AD development in mouse models. This chapter summarizes work implicating the critical role of atypical PKC in the development of liver-dependent hyperinsulinemia as a risk factor in O/T2D-associated AD and β-secretase-mediated pathological alterations in brains of O/T2D-associated and O/T2D-independent AD.
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