Journal of Alzheimer's Disease - Volume 9, issue 2

Authors: DeWitt, David A. | Hurd, Jennifer A. | Fox, Nena | Townsend, Brigitte E. | Griffioen, Kathleen J.S. | Ghribi, Othman | Savory, John

Article Type: Research Article

Abstract: Synapse loss and neuronal death are key features of Alzheimer's disease pathology. Disrupted axonal transport of mitochondria is a potential mechanism that could contribute to both. As the major producer of ATP in the cell, transport of mitochondria to the synapse is required for synapse maintenance. However, mitochondria also play an important role in the regulation of apoptosis. Investigation of aluminum (Al) maltolate induced apoptosis in human NT2 cells led us to explore the relationship between apoptosis related changes and the disruption of mitochondrial transport. Similar to that observed with tau over expression, NT2 cells exhibit peri-nuclear clustering of mitochondria …following treatment with Al maltolate. Neuritic processes largely lacked mitochondria, except in axonal swellings. Similar, but more rapid results were observed following staurosporine administration, indicating that the clustering effect was not specific to Al maltolate. Organelle clustering and transport disruption preceded apoptosis. Incubation with the caspase inhibitor zVAD-FMK effectively blocked apoptosis, however failed to prevent organelle clustering. Thus, transport disruption is associated with the initiation, but not necessarily the completion of apoptosis. These results, together with observed transport defects and apoptosis related changes in Alzheimer disease brain suggest that mitochondrial transport disruption may play a significant role in synapse loss and thus the pathogenesis or Alzheimer's disease. Show more

Keywords: Apoptosis, axonal transport, Alzheimer's disease, aluminum, staurosporine

DOI: 10.3233/JAD-2006-9211

Citation: Journal of Alzheimer's Disease, vol. 9, no. 2, pp. 195-205, 2006

Authors: Blass, John P. | Gibson, Gary E.

Article Type: Research Article

Abstract: Literature values for the correlations between a number of major neurobiological hallmarks of Alzheimer's disease (AD) and the degree of global cognitive impairment among AD patients have been compared, in an attempt to identify biological abnormalities whose treatment might ameliorate the clinical disabilities. High correlations have been described with impairments of cerebral metabolism at both the level of cerebral metabolic rate in vivo and that of mitochondria. The metabolic abnormality develops even before morphological or symptomatic evidence of the illness. Information on such correlations with markers of oxidative stress are not available. Correlations with morphological abnormalities were lower and less …consistent than with brain oxidative metabolism; significant correlations have been observed, in descending order, with a synaptic marker (synaptophysin), with tangle count, and with amyloid. Neither a decrease in a synaptic marker nor in a marker for cholinergic neurons have been found in mild, early AD. Preliminary therapeutic trials of manipulations designed to increase cerebral metabolic rate have given encouraging results, including a trial described briefly in this communication. The clinical value of treatments of the cerebrometabolic deficiency in AD warrants further investigation. Show more

DOI: 10.3233/JAD-2006-9212

Citation: Journal of Alzheimer's Disease, vol. 9, no. 2, pp. 207-218, 2006

Article Type: Discussion

DOI: 10.3233/JAD-2006-9213

Citation: Journal of Alzheimer's Disease, vol. 9, no. 2, pp. 219-224, 2006