Examination of potential mechanisms of amyloid-induced defects in neuronal transport

Shah, Sameer B.; Nolan, Rhiannon; Davis, Emily; Stokin, Gorazd B.; Niesman, Ingrid R.; Canto, Isabel; Glabe, Charles G.; Goldstein, Lawrence S.B.

doi:10.1016/j.nbd.2009.05.016

Cited by 36 publications

(33 citation statements)

References 108 publications

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“…We now show that the oA␤ 1-42 transfer results in a subsequent, slowly developing neurodegeneration that is not observed in cells without oA␤ . The progressive tubulin beading after oA␤ transfer shown here could be a sign of axonal disruption (Shah et al, 2009), indicating that oA␤ can cause axonal damage. Other researchers have proposed that axonal damage is part of the process that leads to neurodegeneration in AD (Pigino et al, 2009), and in concordance with this, a gradually increasing disruption of endosomes, a sign of cytotoxicity (Song et al, 2011), was also observed.…”

Section: Discussionmentioning

confidence: 68%

“…No significant toxicity was observed using an XTT assay, MTT assay, or nuclear staining of oA␤ 1-42 -TMR-loaded donor and acceptor cells after 48 h in coculture (results not shown). Changes in subcellular morphology, such as the formation of beaded tubulin structures (Shah et al, 2009) and changes in the distribution of discrete endosomal protein Rab5a (Song et al, 2011), are early signs of cytotoxicity. Similarly, these measurements indicated that, after Figure 3.…”

Section: Transmission Of Oa␤ Slowly and Gradually Causes Cytotoxicitymentioning

confidence: 99%

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

Nath¹,

Agholme²,

Kurudenkandy³

et al. 2012

Journal of Neuroscience

218

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: Discussionmentioning

confidence: 68%

Section: Transmission Of Oa␤ Slowly and Gradually Causes Cytotoxicitymentioning

confidence: 99%

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

Nath¹,

Agholme²,

Kurudenkandy³

et al. 2012

Journal of Neuroscience

218

222

View full text Add to dashboard Cite

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“…6K, L). This is probably because these fibers arise from affected neurons, although we cannot exclude the possibility that this may be due to the neurotoxic effects of Aβ [6,24,34] . In another study, Meyer-Luehmann et al demonstrated in a mouse model of AD that plaques can grow overnight, with mature plaques originating from smaller amyloid deposits (microplaques) associated with alterations in neighboring neurites [35] .…”

Section: Discussionmentioning

confidence: 99%

The origin and development of plaques and phosphorylated tau are associated with axonopathy in Alzheimer’s disease

Xiao

Wang

et al. 2011

Neurosci. Bull.

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Objective The production of neurotoxic β-amyloid and the formation of hyperphosphorylated tau are thought to be critical steps contributing to the neuropathological mechanisms in Alzheimer's disease (AD). However, there remains an argument as to their importance in the onset of AD. Recent studies have shown that axonopathy is considered as an early stage of AD. However, the exact relationship between axonopathy and the origin and development of classic neuropathological changes such as senile plaques (SPs) and neurofi brillary tangles (NFTs) is unclear. The present study aimed to investigate this relationship. Methods Postmortem tracing, combined with the immunohistochemical or immunofl uorescence staining, was used to detect axonopathy and the formation of SPs and NFTs. Results "Axonal leakage"-a novel type of axonopathy, was usually accompanied with the extensive swollen axons and varicosities, and was associated with the origin and development of Aβ plaques and hyperphosphorylated tau in the brains of AD patients. Conclusion Axonopathy, particularly axonal leakage, might be a key event in the initiation of the neuropathological processes in AD.

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“…9C). Direct contact of the axonal plasma membrane with amyloid fibrils or oligomers could trigger such a block through calcium-mediated signals (53,54) (Fig. 9C).…”

Section: Discussionmentioning

confidence: 99%

Massive accumulation of luminal protease-deficient axonal lysosomes at Alzheimer’s disease amyloid plaques

Gowrishankar

Yuan

et al. 2015

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

316

326

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Through a comprehensive analysis of organellar markers in mouse models of Alzheimer’s disease, we document a massive accumulation of lysosome-like organelles at amyloid plaques and establish that the majority of these organelles reside within swollen axons that contact the amyloid deposits. This close spatial relationship between axonal lysosome accumulation and extracellular amyloid aggregates was observed from the earliest stages of β-amyloid deposition. Notably, we discovered that lysosomes that accumulate in such axons are lacking in multiple soluble luminal proteases and thus are predicted to be unable to efficiently degrade proteinaceous cargos. Of relevance to Alzheimer’s disease, β-secretase (BACE1), the protein that initiates amyloidogenic processing of the amyloid precursor protein and which is a substrate for these proteases, builds up at these sites. Furthermore, through a comparison between the axonal lysosome accumulations at amyloid plaques and neuronal lysosomes of the wild-type brain, we identified a similar, naturally occurring population of lysosome-like organelles in neuronal processes that is also defined by its low luminal protease content. In conjunction with emerging evidence that the lysosomal maturation of endosomes and autophagosomes is coupled to their retrograde transport, our results suggest that extracellular β-amyloid deposits cause a local impairment in the retrograde axonal transport of lysosome precursors, leading to their accumulation and a blockade in their further maturation. This study both advances understanding of Alzheimer’s disease brain pathology and provides new insights into the subcellular organization of neuronal lysosomes that may have broader relevance to other neurodegenerative diseases with a lysosomal component to their pathology.

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Examination of potential mechanisms of amyloid-induced defects in neuronal transport

Cited by 36 publications

References 108 publications

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

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

The origin and development of plaques and phosphorylated tau are associated with axonopathy in Alzheimer’s disease

Massive accumulation of luminal protease-deficient axonal lysosomes at Alzheimer’s disease amyloid plaques

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