Mitochondria-Specific Accumulation of Amyloid β Induces Mitochondrial Dysfunction Leading to Apoptotic Cell Death

Abstract

Mitochondria are best known as the essential intracellular organelles that host the homeostasis required for cellular survival, but they also have relevance in diverse disease-related conditions, including Alzheimer's disease (AD). Amyloid β (Aβ) peptide is the key molecule in AD pathogenesis, and has been highlighted in the implication of mitochondrial abnormality during the disease progress. Neuronal exposure to Aβ impairs mitochondrial dynamics and function. Furthermore, mitochondrial Aβ accumulation has been detected in the AD brain. However, the underlying mechanism of how Aβ affects mitochondrial function remains uncertain, and it is questionable whether mitochondrial Aβ accumulation followed by mitochondrial dysfunction leads directly to neuronal toxicity. This study demonstrated that an exogenous Aβ1–42 treatment, when applied to the hippocampal cell line of mice (specifically HT22 cells), caused a deleterious alteration in mitochondria in both morphology and function. A clathrin-mediated endocytosis blocker rescued the exogenous Aβ1–42-mediated mitochondrial dysfunction. Furthermore, the mitochondria-targeted accumulation of Aβ1–42 in HT22 cells using Aβ1–42 with a mitochondria-targeting sequence induced the identical morphological alteration of mitochondria as that observed in the APP/PS AD mouse model and exogenous Aβ1–42-treated HT22 cells. In addition, subsequent mitochondrial dysfunctions were demonstrated in the mitochondria-specific Aβ1–42 accumulation model, which proved indistinguishable from the mitochondrial impairment induced by exogenous Aβ1–42-treated HT22 cells. Finally, cellular toxicity was directly induced by mitochondria-targeted Aβ1–42 accumulation, which mimics the apoptosis process in exogenous Aβ1–42-treated HT22 cells. Taken together, these results indicate that mitochondria-targeted Aβ1–42 accumulation is the necessary and sufficient condition for Aβ-mediated mitochondria impairments, and leads directly to cellular death rather than along with other Aβ-mediated signaling alterations.

The Neuroprotective Effect of Klotho is Mediated via Regulation of Members of the Redox System

“…The Bcl-2 family of proteins, including Bax and Bim, was implicated in the execution machinery of oA␤-induced neuronal death (71)(72)(73) as well as the alteration of mitochondrial functions (52). The possible regulation of these mechanisms by Klotho requires further investigation.…”

Aβ25–35 Suppresses Mitochondrial Biogenesis in Primary Hippocampal Neurons

“…Our data showed that Ab25-35 induced toxicity in cultured hippocampal neurons, which was consistent with previous studies (Arancibia et al 2008;Dong et al 2010;Resende et al 2007). We and other groups have further demonstrated Ab25-35 caused mitochondrial dysfunction in cultured neurons (Casley et al 2002;Cha et al 2012;Dong et al 2010). In the present study, we found a decrease in mtDNA copy number in cultured hippocampal neurons treated with Ab25-35.…”

“…Xie et al have observed severe structural and functional abnormalities of mitochondria in the immediate vicinity of Ab plaques (Xie et al 2013). Studies using neuronal cell culture demonstrated that Ab causes morphological alteration of mitochondria, ATP depletion, and production of ROS (Casley et al 2002;Cha et al 2012;Chen and Yan 2007;Dong et al 2010). The exposure of isolated mitochondria to Ab reduces complex IV activity (Canevari et al 1999) and induces the formation of the permeability transition pore (Du et al 2008).…”

sCD44 Internalization in Human Trabecular Meshwork Cells

“…33 The internalized receptor cargo is trafficked by localization signals within the ligand/receptor complex. 34 sCD44 internalization may involve mitochondrial dysfunction in a fashion similar to that of b-amyloid fragments, 35,36 causing abnormal mitochondrial function and cell death. The extent of exogenous b-amyloid co-localization in mitochondria is variable from partial without quantification [36][37][38] and 1% to 9%.…”

“…34 sCD44 internalization may involve mitochondrial dysfunction in a fashion similar to that of b-amyloid fragments, 35,36 causing abnormal mitochondrial function and cell death. The extent of exogenous b-amyloid co-localization in mitochondria is variable from partial without quantification [36][37][38] and 1% to 9%. 39 sCD44 is released by proteolytic cleavage 40 (shedding) from membrane-anchored CD44, which influences CD44-mediated HA binding to cell surfaces.…”