. Apolipoprotein E4 Impairs Neuronal Insulin Signaling by Trapping Insulin Receptor in the Endosomes. Neuron. 2017 Sep 27;96(1):115-129.e5. PubMed.


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  1. The paper by Zhao et al. and other earlier findings have shown that ApoE4 impairs neuronal insulin signaling. In the current paper, the authors showed both recombinant ApoE3 and ApoE4 can bind to the insulin receptor, with ApoE4 having higher affinity. But when using brain lysates from ApoE targeted replacement (TR) mice, interaction between ApoE4 and insulin receptor was only observed in old, not young, mice. This is similar to our earlier study (Chan et al., 2015) showing no insulin receptor was associated with affinity-captured-ApoE4 (from ApoE TR mice) in the absence of Aβ peptide. This differential association of insulin receptor with ApoE3 and ApoE4 remained with increasing concentrations of Aβ42. In addition, we also observed that the affinity-captured ApoE4 bound more Aβ42 with increasing peptide levels.

    However, we observed both ApoE3 and ApoE4 hippocampal neurons (from ApoE TR mice) are equally sensitive to physiological levels of insulin. In the presence of Aβ42, insulin failed to elicit a downstream response only in ApoE4 hippocampal neurons.

    Therefore, it will be interesting to examine the effect of Aβ on the entrapment of insulin receptor.


    . Differential interaction of Apolipoprotein-E isoforms with insulin receptors modulates brain insulin signaling in mutant human amyloid precursor protein transgenic mice. Sci Rep. 2015 Sep 8;5:13842. PubMed.

    View all comments by Boon-Seng Wong
  2. This new paper on Alzheimer's disease relates pathogenesis to the aging-related, chronically decreasing ability of glucose to cross the blood-brain barrier. The bulk delivery of glucose through the blood-brain barrier is not insulin dependent. A mouse model of AD with ApoE4 showed 29 percent reduced ability of glucose to cross the BBB compared with the ApoE2 model. I believe this helps explain early onset in people carrying this genetic risk factor. The mechanism by which ApoE4 works is essential to understand, but energy deficiency in CNS may be the key. My paper can be found here


    . Alzheimer's Disease as the Product of a Progressive Energy Deficiency Syndrome in the Central Nervous System: The Neuroenergetic Hypothesis. J Alzheimers Dis. 2017;60(4):1223-1229. PubMed.

    View all comments by Edward Blonz
  3. Zhao et al. report an elegant series of experiments that elucidate mechanisms through which ApoE4 can interfere with brain insulin signaling. Their finding that ApoE4 impairs neuronal insulin signaling by binding to the insulin receptor, accelerating its aggregation and thereby preventing its trafficking from endosomal compartments, represents a significant advance in knowledge about mechanisms underlying the effects of ApoE4 and insulin resistance in the brain. They correctly emphasize the potential importance of this finding for designing therapeutic strategies to restore brain insulin function. However, they carry this argument too far by implying that human APOE4 noncarriers with AD do not have brain insulin resistance, based on their results in the APOE3 mice. Talbot et al. (2012) found evidence of brain insulin resistance in the brains of decedent adults with AD regardless of APOE genotype. A more likely scenario is that APOE4 noncarriers with AD have brain insulin resistance caused by a mechanism unrelated to APOE genotype. For example, disturbed lipid metabolism and vascular dysfunction associated with peripheral insulin resistance in APOE4 noncarriers may impact the brain and induce brain insulin resistance. Similarly, Aβ has been shown to induce brain insulin resistance in rodent and nonhuman primate models, so Aβ dysregulation unrelated to APOE4 could induce brain insulin resistance. Consequently, the authors’ speculation that prolonged treatment with intranasal insulin may not benefit APOE4 noncarriers with AD because they have normal brain insulin sensitivity that will be compromised by treatment-induced brain insulin resistance is unfounded. Studies to date have consistently demonstrated benefits of intranasal regular insulin for non-E4 carriers, although they have been relatively short in duration, with a maximum treatment period of six months. An ongoing Phase 2/3 trial will be completed in 2018, in which participants will receive intranasal insulin or placebo for 12 months, with three-month interval assessments. This study will be adequately powered to determine APOE-associated differences in treatment response over this period, and thus provide more definitive clinical data to address this important question.

    An additional important question is whether the mechanisms underlying brain insulin resistance in APOE3-associated AD differ from the mechanisms demonstrated for APOE4 in the present paper. Different mechanisms may respond better to certain formulations of insulin or different methods of modulating insulin signaling pathways in the brain, and thus such knowledge would enhance our ability to more precisely target prevention and therapeutic strategies. 


    . Intranasal insulin therapy for Alzheimer disease and amnestic mild cognitive impairment: a pilot clinical trial. Arch Neurol. 2012 Jan;69(1):29-38. PubMed.

    . Demonstrated brain insulin resistance in Alzheimer's disease patients is associated with IGF-1 resistance, IRS-1 dysregulation, and cognitive decline. J Clin Invest. 2012 Apr;122(4):1316-38. PubMed.

    View all comments by Suzanne Craft

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  1. ApoE4 Traps Insulin Receptor Inside Neurons