Aberrant stress response associated with severe hypoglycemia in a transgenic mouse model of Alzheimer's disease

Patients with Alzheimer's disease (AD) exhibit alterations in glucose metab olism and dysregulation of the stress-responsive hypothalamic-pituitary-adr enal (HPA) neuroendocrine system. The mechanisms responsible for these alte rations and their possible contributions to the neurodegenerative process i n AD are unknown. We now report that transgenic mice expressing a mutant fo rm of human amyloid precursor protein (APP) that causes inherited early-ons et AD exhibit increased sensitivity to physiological stressors, which is as sociated with aberrancies in HPA function and regulation of blood glucose l evels. Specifically, APP mutant mice exhibit severe hypoglycemia and death following food restriction, and sustained elevations of plasma glucocortico id levels and hypoglycemia following restraint stress. The alterations in H PA function and glucose regulation were evident in relatively young mice pr ior to overt deposition of amyloid beta-peptide (A beta). However, diffuse accumulations of A beta were present in the hypothalamus of older mice, sug gesting a role for soluble forms of A beta in dysregulation of HPA function . Our data demonstrate disturbances in neuroendocrine function in APP mutan t mice similar to those seen in AD patients. These impairments in stress re sponse, glucocorticoid signaling, and regulation of blood glucose should be considered in interpretations of data from past and future studies of APP mutant mice.