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 metabolism and dysregulation of the stress-responsive hypothalamic-pituitary- adrenal (HPA) neuroendocrine system. The mechanisms responsible for these alterations and their possible contributions to the neurodegenerative process in AD are unknown. We now report that transgenic mice expressing a mutant form of human amyloid precursor protein (APP) that causes inherited early- onset AD exhibit increased sensitivity to physiological stressors, which is associated with aberrancies in HPA function and regulation of blood glucose levels. Specifically, APP mutant mice exhibit severe hypoglycemia and death following food restriction, and sustained elevations of plasma glucocorticoid levels and hypoglycemia following restraint stress. The alterations in HPA function and glucose regulation were evident in relatively young mice prior to overt deposition of amyloid β-peptide (Aβ). However, diffuse accumulations of Aβ were present in the hypothalamus of older mice, suggesting a role for soluble forms of Aβ in dysregulation of HPA function. Our data demonstrate disturbances in neuroendocrine function in APP mutant mice similar to those seen in AD patients. These impairments in stress response, glucocorticoid signaling, and regulation of blood glucose should be considered in interpretations of data from past and future studies of APP mutant mice.