Extracellular potassium rapidly inhibits axonal transport of particles in cultured mouse dorsal root ganglion neurites

Hiruma, Hiromi; Nishida, Sanae; Katakura, Takashi; Kusakabe, Tatsumi; Takenaka, Toshifumi; Kawakami, Tadashi

doi:10.1002/(sici)1097-4695(19990205)38:2<225::aid-neu5>3.0.co;2-h

Cited by 4 publications

(1 citation statement)

References 34 publications

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“…While it was generally assumed that Ca 2+ dysregulation and altered activity of neurons at plaques is caused by Aβ oligomers floating in the interstitial fluid, disruptions of glutamatergic signaling also could play a role. In fact, focal increase in glutamatergic drive around plaques is expected not only to drive synaptic hyperactivity and rise of intracellular Ca 2+ but also to initiate degenerative axonal swelling and synaptic loss (Hiruma and others 1999; Hiruma and others 2003). Using a genetically encoded glutamate sensor iGluSnFR, a significant rise of extracellular glutamate level at plaques with reduced glutamate clearance was shown, with disruptive effects on processing of sensory inputs by local circuits (Hefendehl and others 2016).…”

Section: Functional Evidence For Glutamatergic Impairments At Ad Amylmentioning

confidence: 99%

Amyloid Plaques of Alzheimer’s Disease as Hotspots of Glutamatergic Activity

et al. 2018

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Deposition of amyloid plaques in limbic and associative cortices is amongst the most recognized histopathologic hallmarks of Alzheimer's disease. Despite decades of research, there is a lack of consensus over the impact of plaques on neuronal function, with their role in cognitive decline and memory loss undecided. Evidence has emerged suggesting complex and localized axonal pathology around amyloid plaques, with a significant fraction of swellings and dystrophies becoming enriched with putative synaptic vesicles and presynaptic proteins normally colocalized at hotspots of transmitter release. In the absence of hallmark active zone proteins and postsynaptic receptive elements, the axonal swellings surrounding amyloid plaques have been suggested as sites for ectopic release of glutamate, which under reduced clearance can lead to elevated local excitatory drive. Throughout this review, we consider the emerging data suggestive of amyloid plaques as hotspots of compulsive glutamatergic activity. Evidence for local and long-range effects of nonsynaptic glutamate is discussed in the context of circuit dysfunctions and neurodegenerative changes of Alzheimer's disease.

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Section: Functional Evidence For Glutamatergic Impairments At Ad Amylmentioning

confidence: 99%

Amyloid Plaques of Alzheimer’s Disease as Hotspots of Glutamatergic Activity

et al. 2018

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Mechanisms of amyloid plaque pathogenesis

Fiala

2007

Acta Neuropathol

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The first ultrastructural investigations of Alzheimer's disease noted the prominence of degenerating mitochondria in the dystrophic neurites of amyloid plaques, and speculated that this degeneration might be a major contributor to plaque pathogenesis. However, the fate of these organelles has received scant consideration in the intervening decades. A number of hypotheses for the formation and progression of amyloid plaques have since been suggested, including glial secretion of amyloid, somal and synaptic secretion of amyloid-beta protein from neurons, and endosomal-lysosomal aggregation of amyloid-beta protein in the cell bodies of neurons, but none of these hypotheses fully account for the focal accumulation of amyloid in plaques. In addition to Alzheimer's disease, amyloid plaques occur in a variety of conditions, and these conditions are all accompanied by dystrophic neurites characteristic of disrupted axonal transport. The disruption of axonal transport results in the autophagocytosis of mitochondria without normal lysosomal degradation, and recent evidence from aging, traumatic injury, Alzheimer's disease and transgenic mice models of Alzheimer's disease, suggests that the degeneration of these autophagosomes may lead to amyloid production within dystrophic neurites. The theory of amyloid plaque pathogenesis has thus come full circle, back to the intuitions of the very first researchers in the field.

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