fg-9041 and Alzheimer-Disease

The early phase of Alzheimer's disease (AD) is characterized by hippocampus-dependent memory deficits and impaired synaptic plasticity. Increasing evidence suggests that stress and dysregulation of the hypothalamo-pituitary-adrenal (HPA) axis, marked by the elevated circulating glucocorticoids, are risk factors for AD onset. How these changes contribute to early hippocampal dysfunction remains unclear. Using an elaborated version of the object recognition task, we carefully monitored alterations in key components of episodic memory, the first type of memory altered in AD patients, in early symptomatic Tg2576 AD mice. We also combined biochemical and ex vivo electrophysiological analyses to reveal novel cellular and molecular dysregulations underpinning the onset of the pathology. We show that HPA axis, circadian rhythm, and feedback mechanisms, as well as episodic memory, are compromised in this early symptomatic phase, reminiscent of human AD pathology. The cognitive decline could be rescued by subchronic in vivo treatment with RU486, a glucocorticoid receptor antagonist. These observed phenotypes were paralleled by a specific enhancement of N-Methyl-D-aspartic acid receptor (NMDAR)-dependent LTD in CA1 pyramidal neurons, whereas LTP and metabotropic glutamate receptor-dependent LTD remain unchanged. NMDAR transmission was also enhanced. Finally, we show that, as for the behavioral deficit, RU486 treatment rescues this abnormal synaptic phenotype. These preclinical results define glucocorticoid signaling as a contributing factor to both episodic memory loss and early synaptic failure in this AD mouse model, and suggest that glucocorticoid receptor targeting strategies could be beneficial to delay AD onset.

Topics: Alzheimer Disease; Amyloid beta-Protein Precursor; Animals; Dexamethasone; Disease Models, Animal; Excitatory Amino Acid Antagonists; Excitatory Postsynaptic Potentials; Glucocorticoids; Hippocampus; Hormone Antagonists; Humans; Memory Disorders; Memory, Episodic; Mice; Mice, Inbred C57BL; Mice, Transgenic; Mifepristone; Mutation; Neuronal Plasticity; Quinoxalines; Receptors, Glucocorticoid; Recognition, Psychology; Valine

We used primary cultures of cortical neurons to examine the relationship between beta-amyloid toxicity and hyperphosphorylation of the tau protein, the biochemical substrate for neurofibrillary tangles of Alzheimer's brain. Exposure of the cultures to beta-amyloid peptide (betaAP) induced the expression of the secreted glycoprotein Dickkopf-1 (DKK1). DKK1 negatively modulates the canonical Wnt signaling pathway, thus activating the tau-phosphorylating enzyme glycogen synthase kinase-3beta. DKK1 was induced at late times after betaAP exposure, and its expression was dependent on the tumor suppressing protein p53. The antisense induced knock-down of DKK1 attenuated neuronal apoptosis but nearly abolished the increase in tau phosphorylation in betaAP-treated neurons. DKK1 was also expressed by degenerating neurons in the brain from Alzheimer's patients, where it colocalized with neurofibrillary tangles and distrophic neurites. We conclude that induction of DKK1 contributes to the pathological cascade triggered by beta-amyloid and is critically involved in the process of tau phosphorylation.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Amyloid beta-Peptides; Animals; Apoptosis; bcl-2-Associated X Protein; Cells, Cultured; Dizocilpine Maleate; Gene Expression Regulation; Glutamic Acid; Glycogen Synthase Kinase 3; Glycogen Synthase Kinase 3 beta; Humans; Immunoenzyme Techniques; Intercellular Signaling Peptides and Proteins; Nerve Degeneration; Nerve Tissue Proteins; Neurofibrillary Tangles; Neurons; Oligodeoxyribonucleotides; Peptide Fragments; Phosphorylation; Protein Processing, Post-Translational; Proteins; Proto-Oncogene Proteins; Proto-Oncogene Proteins c-bcl-2; Quinoxalines; Rats; RNA, Messenger; Signal Transduction; tau Proteins; Tumor Suppressor Protein p53; Wnt Proteins