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Mitochondrial Aß: a potential focal point for neuronal metabolic dysfunction in Alzheimer’s disease

Casper Caspersen^*,1, Ning Wang^*,,1, Jun Yao^¶, Alexander Sosunov, Xi Chen, Joyce W. Lustbader^||, Hong Wei Xu^**, David Stern, Guy McKhann and Shi Du Yan^*,¶,**,2

^* Departments of Surgery,
Neurosurgery,
Neurology,
^|| Obstetrics and Gynecology,
^¶ Pathology, and
^** Taub Institute for Research on Alzheimer’s disease and the Aging Brain, College of Physicians & Surgeons of Columbia University, New York, New York, USA;
Dean’s Office, College of Medicine, University of Cincinnati, Cincinnati, Ohio, USA; and
Department of Neurology, 1st Affiliated Hospital of Fujian Medical University, Fuzhou, China

²Correspondence: Departments of Surgery, Pathology, and the Taub Institute, College of Physicians & Surgeons of Columbia University, 650 W. 168th St., Black Building, Room 17-07, New York, NY 10032, USA. E-mail: sdy1{at}columbia.edu

SPECIFIC AIMS

There have been many postulated links between mitochondrial function/dysfunction and Alzheimer’s disease (AD) over the years. Recent studies have emphasized a role for intracellular amyloid-ß peptide (Aß) in cytotoxicity of amyloidogenic material. Based on this, we sought to determine whether Aß might be associated with mitochondria.

PRINCIPAL FINDINGS

1. Aß is associated with mitochondria of transgenic (Tg) mice expressing human mutant amyloid precursor protein (mAPP) under control of a promoter directing its expressing to neurons in the central nervous system (PDGF B chain promoter)
Accumulation of Aß occurs in a time-dependent manner (most rapidly during the time interval from 4 to 12 months of age), appears to strongly favor deposition of Aß (1-42) vs. the shorter 40 amino acid forms, and occurs in parts of the brain affected by AD-type pathology. These conclusions result from morphologic (confocal and immunoelectron microscopy) and biochemical (immunoblotting on isolated mitochondria) experiments.

2. Aß associated with mitochondria isolated from Tg mAPP mice appears to be largely within a membrane-associated compartment, based on its continued presence after protease treatment (and disappearance of immunoreactive mitochondrial Aß in the presence of protease plus detergent)

3. Aß is also associated with mitochondria from patients with Alzheimer’s disease compared with nondemented, age-matched controls
The distribution of mitochondrial Aß appears to parallel that of brain regions affected by AD-type pathology, as in the murine model.

4. Mitochondria from Tg mAPP mice harvested at 8 and 12 months of age demonstrated lower levels of oxygen consumption, as well as reduced activity of enzymatic activity associated with respiratory complex III (succinate-cytochrome c reductase) and complex IV (cytochrome c oxidase)

5. Cortical neurons cultured from Tg mAPP mice demonstrate mitochondrial deposition of Aß
In the presence of brefeldin A, an inhibitor of the secretory pathway, the level of mitochondrial Aß appears to increase.

CONCLUSIONS AND SIGNIFICANCE

Our observation that Aß is present within mitochondria may provide a direct link between mitochondrial dysfunction in AD and pathogenic Aß (Fig. 1 ). Aß associated with mitochondria may be deposited at several locations. Although not present exclusively on the outer mitochondrial membrane, Aß that might be present at that site might influence the interaction of multiple cytosolic proteins (including those of the bcl2 family) with mitochondria, as well as affecting the receptor binding of cargo targeted for import into the organelle. In the intramembrane space, Aß might affect the functions of both the inner and outer mitochondrial membrane by multiple mechanisms including modulating their permeability. In the mitochondrial matrix, Aß might interact with important components of metabolic or antioxidant mechanisms. The interaction of Aß with the inner mitochondrial membrane would bring it into contact with respiratory chain complexes with the potential for myriad effects on cellular metabolism. Thus, arrows in Fig. 1 extending to the cytosol indicate that intramitochondrial events are likely to affect events in the cytosol and other cellular compartments. For example, a common consequence of mitochondrial dysfunction is leakage of reactive oxygen species to the cytosol, where they have the capacity to modulate multiple signaling pathways depending on the status of intracellular antioxidant mechanisms.

View larger version (30K): [in this window] [in a new window]   Figure 1. Schematic depiction of a mitochondrion from a Tg mAPP mouse or patient with Alzheimer’s disease with intra-mitochondrial Aß (the relevant Aß-related species are likely to be pathogenic assemblies of Aß42). Aß is shown associated with the outer mitochondrial membrane, inter-membrane space, inner mitochondrial membrane, and in the matrix. The symbol with the question mark associated with Aß in the mitochondrial matrix is meant to indicate the possible association of Aß with cellular targets, such as ABAD (see text). Arrows extending from within mitochondria to the outside (the cytosol) are meant to reflect the likelihood that perturbation of events within the mitochondria will have effects throughout the cell.

On the one hand, these data add to the list of intracellular structures in which Aß has been found, including endoplasmic reticulum/Golgi, lysosomes/endosomes and multivesicular bodies. On the other hand, the presence of Aß within mitochondria poses several questions potentially relevant to the pathobiology of neuronal dysfunction in AD. First, how does Aß gain access to mitochondria? Second, what are the consequences intra-mitochondrial Aß for organelle function? (For example, are there specific macromolecular targets of intracellular Aß?) Third, does the presence of Aß within mitochondria significantly affect cellular functions?

The likely functional significance of mitochondrial Aß for respiratory function is suggested by diminished oxygen consumption as well as enzymatic activity associated with complexes III and IV in mitochondria from Tg mAPP mice compared with nontransgenic littermates. Consistent with this line of reasoning, in a previous study we found that Aß formed a complex with ABAD (Aß binding alcohol dehydrogenase), an enzyme present within the mitochondrial matrix. Based on enzymatic and structural studies, formation of the ABAD-Aß complex inactivated the enzyme, which has the capacity to participate in the metabolism of ketone bodies, the catabolism of isoleucine, and other potentially important metabolic functions. Thus, in this example, mitochondrial Aß may target a particular essential part of the metabolic machinery. It is likely there are multiple intra-mitochondrial targets of Aß yet to be discovered.

Although this view suggests that intramitochondrial Aß might have direct effects, it is also important to consider the possibility that the effect of extracellular Aß (via cellular receptors) and forms of intracellular Aß might influence mitochondrial function indirectly. The key issue is that our current study provides a starting point for examining possible contributions of mitochondrial Aß to the pathogenesis of mitochondrial dysfunction of Aß.

FOOTNOTES

To read the full text of this article, go to http://www.fasebj.org/cgi/doi/10.1096/fj.05-3735fje;

¹ These authors contributed equally to the work.

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