Internalization of β-Amyloid Peptide by Primary Neurons in the Absence of Apolipoprotein E

Saavedra, Lucila; Mohamed, Ahmed F.; Ma, Victoria; Kar, Satyabrata; Chaves, E

doi:10.1074/jbc.m701823200

Cited by 116 publications

(121 citation statements)

References 92 publications

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“…Thus, transmission most likely requires these neuritic connections. This is consistent with previous findings showing that uptake of extracellular A␤ is most efficient in the axon (Saavedra et al, 2007). This phenomenon is thus different from the unspecific uptake used to load the donor cells.…”

Section: Discussionsupporting

confidence: 82%

Spreading of Neurodegenerative Pathology via Neuron-to-Neuron Transmission of -Amyloid

Nath¹,

Agholme²,

Kurudenkandy³

et al. 2012

Journal of Neuroscience

219

222

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Alzheimer's disease (AD) is the major cause of dementia. During the development of AD, neurofibrillary tangles progress in a fixed pattern, starting in the transentorhinal cortex followed by the hippocampus and cortical areas. In contrast, the deposition of ␤-amyloid (A␤) plaques, which are the other histological hallmark of AD, does not follow the same strict spatiotemporal pattern, and it correlates poorly with cognitive decline. Instead, soluble A␤ oligomers have received increasing attention as probable inducers of pathogenesis. In this study, we use microinjections into electrophysiologically defined primary hippocampal rat neurons to demonstrate the direct neuron-to-neuron transfer of soluble oligomeric A␤. Additional studies conducted in a human donor-acceptor cell model show that this A␤ transfer depends on direct cellular connections. As the transferred oligomers accumulate, acceptor cells gradually show beading of tubulin, a sign of neurite damage, and gradual endosomal leakage, a sign of cytotoxicity. These observations support that intracellular A␤ oligomers play a role in neurodegeneration, and they explain the manner in which A␤ can drive disease progression, even if the extracellular plaque load is poorly correlated with the degree of cognitive decline. Understanding this phenomenon sheds light on the pathophysiological mechanism of AD progression. Additional elucidation will help uncover the detailed mechanisms responsible for the manner in which AD progresses via anatomical connections and will facilitate the development of new strategies for stopping the progression of this incapacitating disease.

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Section: Discussionsupporting

confidence: 82%

Spreading of Neurodegenerative Pathology via Neuron-to-Neuron Transmission of -Amyloid

Nath¹,

Agholme²,

Kurudenkandy³

et al. 2012

Journal of Neuroscience

219

222

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“…Hence, THP-1 cells internalize Aβ peptide partly through this pathway. THP-1 cells differ in this property from cultured neurons that show only very little, if any, Aβ uptake by clathrindependent endocytosis (31). Consistent with the relevance of Aβ internalization, SH-SY5Y neuroblastoma cells are found here to possess a relatively low plaque-promoting activity (Fig.…”

Section: Extracellular Aβ Plaques Are Preceded By Intracellular Intersupporting

confidence: 62%

Mechanism of amyloid plaque formation suggests an intracellular basis of Aβ pathogenicity

Friedrich

Tepper²,

Rönicke³

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

284

220

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The formation of extracellular amyloid plaques is a common patho-biochemical event underlying several debilitating human conditions, including Alzheimer’s disease (AD). Considerable evidence implies that AD damage arises primarily from small oligomeric amyloid forms of Aβ peptide, but the precise mechanism of pathogenicity remains to be established. Using a cell culture system that reproducibly leads to the formation of Alzheimer’s Aβ amyloid plaques, we show here that the formation of a single amyloid plaque represents a template-dependent process that critically involves the presence of endocytosis- or phagocytosis-competent cells. Internalized Aβ peptide becomes sorted to multivesicular bodies where fibrils grow out, thus penetrating the vesicular membrane. Upon plaque formation, cells undergo cell death and intracellular amyloid structures become released into the extracellular space. These data imply a mechanism where the pathogenic activity of Aβ is attributed, at least in part, to intracellular aggregates.

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“…Moreover, our confocal microscopy analysis shows that fluorescent A␤ 1-40 applied extracellulary is taken up by the cells and later partly localized to mitochondria. Accordingly, Saavedra and colleagues (34) have recently shown that A␤ 1-42 is internalized by primary neurons in the absence of Apolipoprotein E. These data suggest that secreted A␤ can be reinternalized into cells either itself or through some kind of vesicular transport and come in contact with mitochondria. These mechanisms require further investigation.…”

Section: Fig 2) or Directly To Isolated Mitochondria (Seementioning

confidence: 96%

The amyloid β-peptide is imported into mitochondria via the TOM import machinery and localized to mitochondrial cristae

Petersen

Alikhani²,

Behbahani³

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

619

453

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The amyloid ␤-peptide (A␤) has been suggested to exert its toxicity intracellularly. Mitochondrial functions can be negatively affected by A␤ and accumulation of A␤ has been detected in mitochondria. Because A␤ is not likely to be produced locally in mitochondria, we decided to investigate the mechanisms for mitochondrial A␤ uptake. Our results from rat mitochondria show that A␤ is transported into mitochondria via the translocase of the outer membrane (TOM) machinery. The import was insensitive to valinomycin, indicating that it is independent of the mitochondrial membrane potential. Subfractionation studies following the import experiments revealed A␤ association with the inner membrane fraction, and immunoelectron microscopy after import showed localization of A␤ to mitochondrial cristae. A similar distribution pattern of A␤ in mitochondria was shown by immunoelectron microscopy in human cortical brain biopsies obtained from living subjects with normal pressure hydrocephalus. Thus, we present a unique import mechanism for A␤ in mitochondria and demonstrate both in vitro and in vivo that A␤ is located to the mitochondrial cristae. Importantly, we also show that extracellulary applied A␤ can be internalized by human neuroblastoma cells and can colocalize with mitochondrial markers. Together, these results provide further insight into the mitochondrial uptake of A␤, a peptide considered to be of major significance in Alzheimer's disease.Alzheimer disease ͉ protein import ͉ human brain biopsies T he amyloid-␤ peptide (A␤) is produced by regulated intramembrane proteolysis of the A␤ precursor protein (APP) by the sequential cleavage by ␤-and ␥-secretases (1-2). Plaques consisting mainly of aggregated A␤ are detected in the neuropil in aged subjects and in particular in subjects with Alzheimer's disease (AD) (3-5). Recently, it has been argued that it is A␤ oligomers and fibrils that cause toxicity, loss of synapses, and ultimately neuronal death (6-9). The exact mechanisms of how A␤ damages the neurons are still unknown; however, several lines of evidence implicate that A␤ exerts its toxicity intracellularly (10, 11) and point toward a role of mitochondria in this process (12). It has been reported that mitochondrial A␤ accumulation impairs neuronal function and, thus, contributes to cellular dysfunction in a transgenic APP mouse model (13). It is noteworthy that in AD at an early stage there is already a reduction in the number of mitochondria (14), the brain glucose metabolism is decreased (15), and the activities of both tricarboxylic acid cycle enzymes (16) and cytochrome c oxidase (COX) are reduced (17)(18)(19)(20). In vitro studies with isolated mitochondria suggest that A␤ 1-42 inhibits COX activity in a copper-dependent manner (21). Furthermore, mitochondrial A␤-binding alcohol dehydrogenase (ABAD) has been found to be up-regulated in neurons from AD patients (22), and A␤ has been shown to interact with ABAD, resulting in free radical production and neuronal apoptosis. Recently, we have shown that preseque...

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Internalization of β-Amyloid Peptide by Primary Neurons in the Absence of Apolipoprotein E

Cited by 116 publications

References 92 publications

Spreading of Neurodegenerative Pathology via Neuron-to-Neuron Transmission of -Amyloid

Spreading of Neurodegenerative Pathology via Neuron-to-Neuron Transmission of -Amyloid

Mechanism of amyloid plaque formation suggests an intracellular basis of Aβ pathogenicity

The amyloid β-peptide is imported into mitochondria via the TOM import machinery and localized to mitochondrial cristae

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