Abstract
ß-amyloid (Aß1−42) is produced by proteolytic cleavage of the transmembrane type-1 protein, amyloid precursor protein. Under pathological conditions, Aß1−42self-aggregates into oligomers, which cause synaptic dysfunction and neuronal loss, and are considered the culprit of Alzheimer's disease (AD). However, Aß1−42 is mainly monomeric at physiological concentrations, and the precise role of monomeric Aß1−42 in neuronal function is largely unknown. We report that the monomer of Aß1−42 activates type-1 insulin-like growth factor receptors and enhances glucose uptake in neurons and peripheral cells by promoting the translocation of the Glut3 glucose transporter from the cytosol to the plasma membrane. In neurons, activity-dependent glucose uptake was blunted after blocking endogenous Aß production, and re-established in the presence of cerebrospinal fluid Aß. APP-null neurons failed to enhance depolarization-stimulated glucose uptake unless exogenous monomeric Aß1−42 was added. These data suggest that Aß1−42 monomers were critical for maintaining neuronal glucose homeostasis. Accordingly, exogenous Aß1−42 monomers were able to rescue the low levels of glucose consumption observed in brain slices from AD mutant mice.
Highlights
Sporadic age-related form of Alzheimer’s disease (AD) is the most frequent yet incurable type of dementia
Synthetic Ac-KLVFF-NH2 maintained into a monomeric form (Supplemental Figure 1A) shared the protective activity of monomeric Aß1−42,and its action was prevented by the insulin/insulin-like growth factor 1 (IGF-1) receptor inhibitor, AG1024, or by the selective type-1 IGF receptor (IGF-insulin receptor (IR)) inhibitor, PPP (Figures 1A,B)
We have previously shown that monomeric Aß1−42 has a broad neuroprotective activity, which is sensitive to inhibitors of insulin/IGF-1 signaling (Giuffrida et al, 2009)
Summary
Difficulties in advancing disease understanding and clinical interventions partly depend on complex interactions between disease determinants, namely the toxic ß-amyloid− (Aß1−42) species (Selkoe, 2011), and age-related risk factors, including the decline of insulin-like growth factor 1 (IGF-1) functions (Piriz et al, 2011), and the occurrence of peripheral insulin resistance or diabetes (Jayaraman and Pike, 2014) These intervening factors, among others, might progressively overcome the Metabolic IGF-1-like actions of Aß(1-42) monomers ability of the brain cognitive reserve to buffer the impact of the pathology on cognitive functions. We suggest that a defective IGF-IR signaling contributes to AD progression via a disease-specific mechanism involving the loss of receptor activation by Aß monomers, which become depleted when pathological aggregates are formed
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