Mitochondrial abnormalities in neuroectodermal cells stably expressing human amyloid precursor protein (hAPP751)

Abstract

Metabolic hypofunction is a common finding in a number of neurodegenerative diseases, including Alzheimer's disease (AD). The strong linkage between the amyloid precursor protein (APP) and AD led us to examine whether over-expression of this protein in CNS-type cells had an effect on mitochondria. We found abnormal morphology in mitochondria of the neuroectodermal progeny of P19 cells stably transfected with human APP751. In addition, the mitochondria of APP-transfected clones had a decreased mitochondrial membrane potential. These changes were independent of Abeta toxicity and distinct from complex I inhibition. Our results have important implications for the earliest events in the pathophysiology of AD and, by extrapolation, for intervention therapies.

Tunneling-nanotube development in astrocytes depends on p53 activation

“…17 Overexpressing human APP751 in P19 cells caused an increase in intracellular Ab level associating with a decrease in mitochondria membrane potential. 18 A strong piece of direct evidence for intracellular Ab cytotoxicity came from an experiment in which microinjection of Ab 1À42 induced significant cell death in human primary cultured neurons. 19 When intracellularly expressed fusion protein Ab-EGFP was transfected into rat astrocytes (Figure 3a) or microinjected into rat neurons (Figure 3c), the spreading of EGFP to another cells was observed 30 min after transfection or microinjection (Figures 3b and d), suggesting that intracellular Ab could use TNTs to transfer to another cell.…”

β-Secretase-Cleaved Amyloid Precursor Protein Accumulates at Actin Inclusions Induced in Neurons by Stress or Amyloid β: A Feedforward Mechanism for Alzheimer's Disease

“…Therefore, A␤ peptides may induce activation of specific signaling pathways in a subpopulation of normal neurons that results in enhanced ADF/cofilin activity. In addition, A␤ has been shown to have detrimental effects on mitochondria (Grant et al, 1999;Anandatheerthavarada et al, 2003;Lustbader et al, 2004;Mattson, 2004), and there may exist a neuronal subpopulation in which mitochondria are extremely sensitive to A␤. The ability to visualize rod-containing neurons in live cells expressing fluorescent protein chimeras of ADF/cofilin offers an opportunity to isolate and characterize this selective neuronal population.…”

Impact of Intracellular β-Amyloid in Transgenic Animals and Cell Models

“…We have observed early on that abnormal iA ␤ accumulation in amyloid precursor protein stably transfected cells is accompanied by mitochondrial pathology, including a shift to lower mitochondrial membrane potentials [21] ; this was also later observed in dissociated embryonic cortical neurons from DS cases [22] . The involvement of mitochondria is of particular interest, since A ␤ accumulation in these organelles is associated with a reduction in oxygen consumption rate [23] , leading to the formation of free radicals and neuronal cell death [24] .…”