ABSTRACT
BACKGROUND: Many identified mechanisms could be upstream of the prominent amyloid-ß (Aß) plaques in Alzheimer's disease (AD). OBJECTIVE: To profile the progression of pathology in AD. METHODS: We monitored metabolic signaling, redox stress, intraneuronal amyloid-ß (iAß) accumulation, and extracellular plaque deposition in the brains of 3xTg-AD mice across the lifespan. RESULTS: Intracellular accumulation of aggregated Aß in the CA1 pyramidal cells at 9 months preceded extracellular plaques that first presented in the CA1 at 16 months of age. In biochemical assays, brain glutathione (GSH) declined with age in both 3xTg-AD and non-transgenic controls, but the decline was accelerated in 3xTg-AD brains from 2 to 4 months. The decline in GSH correlated exponentially with the rise in iAß. Integrated metabolic signaling as the ratio of phospho-Akt (pAkt) to total Akt (tAkt) in the PI3kinase and mTOR pathway declined at 6, 9, and 12 months, before rising at 16 and 20 months. These pAkt/tAkt ratios correlated with both iAß and GSH levels in a U-shaped relationship. Selective vulnerability of age-related AD-genotype-specific pAkt changes was greatest in the CA1 pyramidal cell layer. To demonstrate redox causation, iAß accumulation was lowered in cultured middle-age adult 3xTg-AD neurons by treatment of the oxidized redox state in the neurons with exogenous cysteine. CONCLUSION: The order of pathologic progression in the 3xTg-AD mouse was loss of GSH (oxidative redox shift) followed by a pAkt/tAkt metabolic shift in CA1, iAß accumulation in CA1, and extracellular Aß deposition. Upstream targets may prove strategically more effective for therapy before irreversible changes.