Abstract
Increasing epidemiological evidence highlights the association between systemic insulin resistance and Alzheimer’s disease (AD). As insulin resistance can be caused by high-stress hormone levels and since hypercortisolism appears to be an important risk factor of AD, we aimed to investigate the systemic insulin functionality and circulating stress hormone levels in a mutant humanized amyloid precursor protein (APP) overexpressing (hAPP23+/−) AD mouse model. Memory and spatial learning of male hAPP23+/− and C57BL/6 (wild type, WT) mice were assessed by a Morris Water Maze (MWM) test at the age of 4 and 12 months. The systemic metabolism was examined by intraperitoneal glucose and insulin tolerance tests (GTT, ITT). Insulin and corticosterone levels were determined in serum. In the hippocampus, parietal and occipital cortex of hAPP23+/− brains, amyloid-beta (Aβ) deposits were present at 12 months of age. MWM demonstrated a cognitive decline in hAPP23+/− mice at 12 but not at 4 months, evidenced by increasing total path lengths and deteriorating probe trials compared to WT mice. hAPP23+/− animals presented increased serum corticosterone levels compared to WT mice at both 4 and 12 months. hAPP23+/− mice exhibited peripheral insulin resistance compared to WT mice at 4 months, which stabilized at 12 months of age. Serum insulin levels were similar between genotypes at 4 months of age but were significantly higher in hAPP23+/− mice at 12 months of age. Peripheral glucose homeostasis remained unchanged. These results indicate that peripheral insulin resistance combined with elevated circulating stress hormone levels could be potential biomarkers of the pre-symptomatic phase of AD.
Highlights
Our data show the pre-symptomatic presence of peripheral insulin resistance in hAPP23+/− mice, in the absence of T2DM, which eventually evolves into hyperinsulinemia in a symptomatic phase of the Alzheimer’s disease (AD) pathogenesis
We found an association between the stress hormone corticosterone and insulin resistance as a feature of hypermetabolism in these animals
These observations indicate the presence of elevated stress hormone levels, insulin resistance, and other observable hypermetabolic features as potential non-invasive biomarkers for the early detection of the AD pathophysiology
Summary
Additional diagnostic tests in clinical routine practice entail the use of the core AD cerebral spinal fluid (CSF) biomarkers, i.e., phosphorylated TAU, total TAU, and the Aβ1–42 /Aβ1–40 ratio [3]. These diagnostic tools are both invasive and expensive and are usually only given to patients who are already showing clear symptoms of the disease. Insulin resistance was long considered a central feature of type II diabetes mellitus (T2DM), previous studies showed its contribution and presence in the AD brain in the absence of T2DM [17]. Additional studies in AD patients have demonstrated an association between insulin levels and cerebral amyloid deposition, and, importantly, hyperinsulinemia doubles the risk of developing AD [18,19]
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