Effect of energy deficiency on the accumulation of Aβ and phosphorylation of tau

  • 李 竹菀

Student thesis: Doctoral Thesis

Abstract

Alzheimer’s disease (AD) is an age-related neurodegenerative disease AD occurs gradually and results in memory loss behavior and personality changes and a decline in thinking abilities Pathologically AD is characterized by intracellular aggregation of neurofibrillary tangles and extracellular deposition of amyloid plaque The amyloid plaques primarily consist of β-Amyloid (Aβ) peptides and the neurofibrillary tangles comprise of hyperphosphorylated tau proteins Results from epidemiological and pathological research showed a strong link between cardiovascular diseases and AD It has been suggested that chronic brain hypoperfusion is the common denominator among cardiovascular diseases One major consequence of hypoperfusion is insufficient supply of glucose to brain hence results in cerebral hypometabolism However whether energy deficiency contributes to the development of AD remains unclear To investigate the causal relationship we performed the following three experiments 1) We cultured the differentiated N2a neuroblastoma cells in media containing no glucose or pyruvate (NGM) Shortly after the N2a cells cultured in the NGM the mitochondria membrane potential was reduced and the AMP-activated-protein-kinase (AMPK) an energy sensor was activated Treatment of NGM not only increased the levels of tau phosphorylation at Ser262 and Ser396 but also increased the levels of active forms of GSK3? and GSK3β two major tau kinases 2) The effect of energy deficiency was further examined in vivo by intracerebroventricular (icv) injection of streptozotocin (STZ) to the Wistar rats STZ selectively injuries glucose transporter type 2-bearing cells which are primarily astrocytes in the rat brain hence interrupts glucose transportation from blood vessel to neuron STZ-icv injection induced energy crisis in the brain regions surrounding the ventricles as indicated by elevated pAMPK levels in the hippocampus STZ-icv treatment increased the levels of phosphorylated tau and activated GSK3β in the hippocampus The hippocampus-dependent spatial learning and memory was impaired by the STZ-icv treatment 3) Because the levels of Aβ in the N2a cells and Wistar rats were too low to be accurately quantified we therefore used human amyloid precursor protein overexpressed N2a cells (APP cells) to investigate the effect of energy deficiency on Aβ production The results showed that concentrations of glucose in culture media negatively associated with the levels of pAMPK in the APP cells but positively correlated with the levels of Aβ in the condition media When APP cells were cultured in glucose-containing media drug-induced activation of AMPK decreased the levels of Aβ in the condition media However if APP cells were incubated in media containing no glucose inhibition of AMPK activity increased the levels of Aβ while the levels of full-length APP APP? APPβ APP C-terminal fragment ? and C-terminal fragment β were unchanged Taken together these studies suggest that energy deficiency increases the levels of tau phosphorylation Furthermore when energy is deficient and AMPK activation is inhibited the levels of Aβ are increased probably due to reduced clearance of Aβ Thus our studies support the premise that metabolic disorders contribute to AD pathogenesis
Date of Award2014 Aug 19
Original languageEnglish
SupervisorYu-Min Kuo (Supervisor)

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