Activation of Neuronal Defense Mechanisms in Response to Pathogenic Factors Triggering Induction of Amyloidosis in Alzheimer's Disease

作者：Maltsev Alexander V^*; Santockyte Rasa; Bystryak Simon; Galzitskaya Oxana V

来源：Journal of Alzheimer's Disease, 2014, 40(1): 19-32.

DOI：10.3233/JAD-131562

• Alzheimer's disease
• amyloid-beta protein precursor
• amyloidosis
• cellular defense factors
• hyperphosphorylation
• neuron loss
• phosphorylation
• tau protein

We present a new model for etiology of Alzheimer's disease (AD) which postulates early involvement of specialized neuroprotective mechanisms in the pathology of AD. These neuroprotective mechanisms work in concert to regulate metabolic homeostasis in healthy neuronal cells, but contribute to the distinctive cytopathic phenotype of neuronal degeneration in AD. According to this model, two molecular/genetic hallmarks of AD, amyloid-beta (A beta) deposition and tau hyperphosphorylation, are associated with neuronal mechanisms for dissipating thermal energy associated with high levels of protein synthesis in highly temperature-sensitive neuronal cells. Development of effective methods of AD treatment will require a better understanding of how this neuronal defense system is activated in response to cytopathological triggers in sporadic AD. The cause and effect link between synthesis and processing of amyloid-beta protein precursor (A beta PP) and the AD terminal phenotype of neurofibrillary tangles and neuron loss involve the formation of A beta peptides that accumulate as oligomers, cannot be controlled by neurons, and are toxic to the surrounding neuronal membranes. We analyze experimental and clinical studies that have investigated the correlation between phosphorylation of some transport proteins and increased synthesis of proteins in neurons. We also review the evidence related to the possibility that protein hyperphosphorylation may be a byproduct of energetic imbalances in AD cells associated with high levels of protein synthesis, and that activation of defense systems, through which energy-rich molecules are eliminated from the site of protein synthesis and are sequestered to the peripheral neuronal areas, may bring about some of the distinctive morphological features of AD.

• 出版日期2014