Axonal degeneration in Alzheimer's disease: When signaling abnormalities meet the axonal transport system

Kanaan, Nicholas M.; Pigino, Gustavo; Brady, Scott T.; Lazarov, Orly; Binder, Lester I.; Morfini, Gerardo

doi:10.1016/j.expneurol.2012.06.003

Cited by 186 publications

(163 citation statements)

References 145 publications

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“…44,45 Much evidence points, however, to dying-back axonal degeneration due to axoplasmic transport defects induced by pathological tau as a physiopathological mechanism in Alzheimer disease. 46 Consistently, the alterations at the level of the NMJ in Tg30tau mice illustrate a toxic effect of abnormal tau at the presynaptic level. A recent study also pointed to disturbances at the presynaptic level in mossy fibers in the hippocampus in a tauopathy model.…”

Section: Muscle Denervation In a Tauopathy Modelmentioning

confidence: 78%

Motor Deficit in a Tauopathy Model Is Induced by Disturbances of Axonal Transport Leading to Dying-Back Degeneration and Denervation of Neuromuscular Junctions

Audouard¹,

Hees²,

Suain³

et al. 2015

The American Journal of Pathology

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Several neurodegenerative diseases are characterized by both cognitive and motor deficits associated with accumulation of tau aggregates in brain, brainstem, and spinal cord. The Tg30 murine tauopathy model expresses a human tau protein bearing two frontotemporal dementia with Parkinsonism linked to chromosome 17 pathogenic mutations and develops a severe motor deficit and tau aggregates in brain and spinal cord. To investigate the origin of this motor deficit, we analyzed the age-dependent innervation status of the neuromuscular junctions and mutant tau expression in Tg30 mice. The human transgenic tau was detected from postnatal day 7 onward in motoneurons, axons in the sciatic nerve, and axon terminals of the neuromuscular junctions. The development and maturation of neuromuscular junctions were not disrupted in Tg30 mice, but their maintenance was disturbed in adult Tg30 mice, resulting in a progressive and severe muscle denervation. This muscle denervation was associated with early electrophysiological signs of muscle spontaneous activities and histological signs of muscle degeneration. Early loss of synaptic vesicles in axon terminals preceding motor deficits, accumulation of Gallyas-positive aggregates, and cathepsin-positive vesicular clusters in axons in the sciatic nerve suggest that this denervation results from disturbances of axonal transport. This physiopathological mechanism might be responsible for motor signs observed in some human tauopathies, and for synaptic dysfunction resulting from alterations at the presynaptic level in these diseases. (Am J Pathol 2015 http://dx

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Section: Muscle Denervation In a Tauopathy Modelmentioning

confidence: 78%

Motor Deficit in a Tauopathy Model Is Induced by Disturbances of Axonal Transport Leading to Dying-Back Degeneration and Denervation of Neuromuscular Junctions

Audouard¹,

Hees²,

Suain³

et al. 2015

The American Journal of Pathology

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“…These "signaling endosomes" are then retrogradely transported to the corresponding cell bodies to transmit NGF trophic signals (50,98). Thus, axonal trafficking mediated by Rab5 + endosomes plays a critical role in maintaining the trophic status of BFCNs, and alteration in these aspects could potentially disrupt axonal transport, resulting in neurodegenerative disorders (88,(99)(100)(101)(102)(103)(104)(105)(106)(107).…”

Section: Discussionmentioning

confidence: 99%

Amyloid precursor protein–mediated endocytic pathway disruption induces axonal dysfunction and neurodegeneration

Xu¹,

Weissmiller²,

White³

et al. 2016

Journal of Clinical Investigation

152

225

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R e s e a R c h a R t i c l e1 8 1 6jci.org Volume 126Number 5 May 2016 26, 54, 55). We assayed the level of GTP-Rab5 in brains of 12-monthold Ts65Dn and 2N mice following a published protocol (56). As previously reported (28), the level of full-length APP in Ts65Dn was approximately 1.5-fold than in 2N samples ( We next tested whether the increase in App gene dose in Ts65Dn BFCNs was responsible for enlargement of Rab5 + endosomes (Figure 1). By immunoblotting, the APP siRNA caused an approximately 30% reduction in the level of full-length APP, as compared with control siRNA ( Figure 2E). Rab5 + puncta in BFCNs treated with either the APP siRNA or control siRNA were analyzed (Figure 2, F and G) as in Figure 1. Large, sometimes lobulated Rab5 + puncta were seen in cultures treated with the control siRNA, whereas these structures were typically smaller and rounded in cultures treated with the APP siRNA ( Figure 2G). Treatment with the APP siRNA significantly reduced the size of Rab5 + puncta in Ts65Dn neurons to a value equivalent to that in 2N neurons ( Figure 2F). Thus, increased App gene dose is necessary for increased Rab5 activation and for early endosome enlargement in Ts65Dn neurons.Full-length APP and β-CTF caused enlargement of early endosomes in PC12 cells. To determine how increased APP expression caused an increase in Rab5 activation, we asked which APP product(s) were responsible (Supplemental Figure 1A). We transfected PC12M cells with full-length APP-GFP, C99-GFP (β-CTF), C83-GFP (α-CTF), or AICD-GFP and examined endosomes by live cell imaging (Supplemental Figure 1B). Bright foci of GFP + intracellular structures were present in PC12M cells that overexpressed APP-GFP or C99-GFP. In contrast, cells expressing C83-GFP or AICD-GFP showed diffuse, hazy signals for GFP, with occasional foci in C83-GFP cells. In APP-GFP and C99-GFP cells, the GFP + intracellular structures were, on average, approximately 2 μm 2 (Supplemental Figure 1E). GFP signals in C83-GFP or AICD-GFP cells contained speckled small puncta within the haze, as well as a small number of larger bright puncta, as seen in cells expressing C99-GFP and APP-GFP (Supplemental Figure 1B). However, the average puncta size in C83-GFP and AICD-GFP cells was approximately 1.2 and 1.3 μm 2 , respectively. Thus, overexpressing APP and β-CTF, but not α-CTF or AICD, routinely induced formation of enlarged, bright intracellular structures. We also tested two APP mutants: APP M596V and APP SWE . APP M596V , which abolishes β-secretase cleavage, prevents production of β-CTF (57); APP SWE enhances β-secretase cleavage to increase the level of β-CTF (57). Both induced the formation of enlarged intracellular structures (Supplemental Figure 1C).We examined colocalization of APP or C99 with Rab5 in cotransfection experiments; APP-mCherry with GFP-Rab5 WT ( Figure 3B); C99-GFP with mCherry-Rab5 WT ( Figure 3C); and Rab5 + endosomes (26, 28, 37) was correlated with reduced endosomal trafficking and signaling of nerve growth factor (NGF), leading to degeneration...

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“…In neurodegenerative diseases, neuronal networks are believed not spontaneously regenerated by distinct causes; for example, amyloid β (Aβ) induces axonal atrophy in Alzheimer's disease, and inhibitory proteoglycans inhibit regeneration of axons in spinal cord injury. [1][2][3][4][5][6][7][8][9][10] Although several drugs are clinically used for the treatment of neurodegenerative diseases, most of these drugs are for symptomatic treatment; drugs for fundamental cure of neurodegenerative diseases are not clinically available and greatly needed.…”

Section: Introductionmentioning

confidence: 99%

Effects of Ashwagandha (Roots of <i>Withania somnifera</i>) on Neurodegenerative Diseases

Kuboyama

Tohda

Komatsu

2014

Biological & Pharmaceutical Bulletin

121

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Neurodegenerative diseases commonly induce irreversible destruction of central nervous system (CNS) neuronal networks, resulting in permanent functional impairments. Effective medications against neurodegenerative diseases are currently lacking. Ashwagandha (roots of Withania somnifera DUNAL) is used in traditional Indian medicine (Ayurveda) for general debility, consumption, nervous exhaustion, insomnia, and loss of memory. In this review, we summarize various effects and mechanisms of Ashwagandha extracts and related compounds on in vitro and in vivo models of neurodegenerative diseases such as Alzheimer's disease and spinal cord injury.

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Axonal degeneration in Alzheimer's disease: When signaling abnormalities meet the axonal transport system

Cited by 186 publications

References 145 publications

Motor Deficit in a Tauopathy Model Is Induced by Disturbances of Axonal Transport Leading to Dying-Back Degeneration and Denervation of Neuromuscular Junctions

Motor Deficit in a Tauopathy Model Is Induced by Disturbances of Axonal Transport Leading to Dying-Back Degeneration and Denervation of Neuromuscular Junctions

Amyloid precursor protein–mediated endocytic pathway disruption induces axonal dysfunction and neurodegeneration

Effects of Ashwagandha (Roots of <i>Withania somnifera</i>) on Neurodegenerative Diseases

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