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

Xiao, Ai-Wu; He, J. P.; Wang, Qian; Luo, Yi; Sun, Yan; Zhou, Yanping; Guan, Yang; Lucassen, Paul J.; Dai, Jiapei

doi:10.1007/s12264-011-1736-7

Cited by 34 publications

(31 citation statements)

References 41 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Complementing these findings, Xiao and colleagues recently showed that extensively swollen axons and varicosities, accompanied by pronounced axonal leakage, are associated with the origin and development of neuritic plaques in patients with AD 28 (Figure 2a,b). Swollen axons and varicosities in patients with AD contain high levels of APP 28 and autophagic vacuoles that are enriched in PS1, 123 cathepsin-D and cathepsin-B 124 -lysosomal proteases with β-secretase activity 125 -as well as other lysosomal proteins. It is plausible, therefore, that the release of intracellular contents into the extracellular matrix via axonal leakage 28 could bring APP into close proximity with APP-specific proteases.…”

Section: From Varicosities To Degenerationmentioning

confidence: 66%

“…17 Finally, these APP accumulations might represent a seed for other aggregation-prone peptides ( Figure 1, step 5), as demonstrated in immune-challenged transgenic AD mice. 17 On the basis of recent observations in the brains of patients with AD, 28 we propose that axonal leakage and release of intracellular contents-especially from dense auto phagolysosomal vesicles 30 32 and diverse non-Aβ fragments of APP 33,34 in senile plaques. In addition, electron micro scopy of human senile plaques revealed, in accordance with this proposal, an abundance of mitochondria and other organelles, as well as degenerated neurites, in the plaque core.…”

Section: Inflammation Hypothesis Of Admentioning

confidence: 95%

“…17 This outcome would lead to further impairments in axonal transport, complete transport blockade, and ultimately axonal leakage ( Figure 1, step 4; Figure 2a). 28 Loss of synaptic contacts and decline in cognitive performance constitute additional structural and functional consequences of axonal transport impairments ( Figure 1, step 4). 17,29 A chronic inflammatory state also increases APP levels, 17 which may be followed by accumulation of this protein in swollen axons ( Figure 1, steps 2-4; Figure 2b).…”

Section: Inflammation Hypothesis Of Admentioning

confidence: 99%

“…17,29 A chronic inflammatory state also increases APP levels, 17 which may be followed by accumulation of this protein in swollen axons ( Figure 1, steps 2-4; Figure 2b). 28 In parallel with its effect on neurons, chronic systemic inflammation induces a prominent activation, or 'priming' , of microglial cells and extensive astrogliosis (Figure 1, step 3). 17 Recruitment of microglia towards degenerative and/or leaking axons and axonal varicosities could, therefore, lead to over-activation of microglia and production of local inflammatory 'hot spots' that would also be expected to negatively affect nearby neurons ( Figure 1, step 5).…”

Section: Inflammation Hypothesis Of Admentioning

confidence: 99%

“…Swollen axons and varicosities in patients with AD contain high levels of APP 28 and autophagic vacuoles that are enriched in PS1, 123 cathepsin-D and cathepsin-B 124 -lysosomal proteases with β-secretase activity 125 -as well as other lysosomal proteins. It is plausible, therefore, that the release of intracellular contents into the extracellular matrix via axonal leakage 28 could bring APP into close proximity with APP-specific proteases. Aberrant APP processing at these locations is in agreement with the findings that Aβ plaques in patients with AD contain not only Aβ and Aβ , but also substantial amounts of truncated Aβ peptides, 32 as well as large amounts of APP and its non-amyloidogenic fragments.…”

Section: From Varicosities To Degenerationmentioning

confidence: 99%

See 4 more Smart Citations

Deciphering the mechanism underlying late-onset Alzheimer disease

2012

View full text Add to dashboard Cite

Despite tremendous investments in understanding the complex molecular mechanisms underlying Alzheimer disease (AD), recent clinical trials have failed to show efficacy. A potential problem underlying these failures is the assumption that the molecular mechanism mediating the genetically determined form of the disease is identical to the one resulting in late-onset AD. Here, we integrate experimental evidence outside the 'spotlight' of the genetic drivers of amyloid-(A) generation published during the past two decades, and present a mechanistic explanation for the pathophysiological changes that characterize late-onset AD. We propose that chronic inflammatory conditions cause dysregulation of mechanisms to clear misfolded or damaged neuronal proteins that accumulate with age, and concomitantly lead to tau-associated impairments of axonal integrity and transport. Such changes have several neuropathological consequences: focal accumulation of mitochondria, resulting in metabolic impairments; induction of axonal swelling and leakage, followed by destabilization of synaptic contacts; deposition of amyloid precursor protein in swollen neurites, and generation of aggregation-prone peptides; further tau hyperphosphorylation, ultimately resulting in neurofibrillary tangle formation and neuronal death. The proposed sequence of events provides a link between A and tau-related neuropathology, and underscores the concept that degenerating neurites represent a cause rather than a consequence of A accumulation in late-onset AD. Abstract | Despite tremendous investments in understanding the complex molecular mechanisms underlying Alzheimer disease (AD), recent clinical trials have failed to show efficacy. A potential problem underlying these failures is the assumption that the molecular mechanism mediating the genetically determined form of the disease is identical to the one resulting in late-onset AD. Here, we integrate experimental evidence outside the 'spotlight' of the genetic drivers of amyloid-β (Aβ) generation published during the past two decades, and present a mechanistic explanation for the pathophysiological changes that characterize late-onset AD. We propose that chronic inflammatory conditions cause dysregulation of mechanisms to clear misfolded or damaged neuronal proteins that accumulate with age, and concomitantly lead to tau-associated impairments of axonal integrity and transport. Such changes have several neuropathological consequences: focal accumulation of mitochondria, resulting in metabolic impairments; induction of axonal swelling and leakage, followed by destabilization of synaptic contacts; deposition of amyloid precursor protein in swollen neurites, and generation of aggregation-prone peptides; further tau hyperphosphorylation, ultimately resulting in neurofibrillary tangle formation and neuronal death. The proposed sequence of events provides a link between Aβ and tau-related neuropathology, and underscores the concept that degenerating neurites represent a cause rather than a consequence ...

show abstract

Section: From Varicosities To Degenerationmentioning

confidence: 66%

Section: Inflammation Hypothesis Of Admentioning

confidence: 95%

Section: Inflammation Hypothesis Of Admentioning

confidence: 99%

Section: Inflammation Hypothesis Of Admentioning

confidence: 99%

Section: From Varicosities To Degenerationmentioning

confidence: 99%

See 3 more Smart Citations

Deciphering the mechanism underlying late-onset Alzheimer disease

2012

View full text Add to dashboard Cite

show abstract

Nmnat1 protects neuronal function without altering phospho‐tau pathology in a mouse model of tauopathy

Musiek¹,

Xiong²,

Patel³

et al. 2016

Ann Clin Transl Neurol

View full text Add to dashboard Cite

ObjectiveThe nicotinamide‐nucleotide adenylyltransferase protein Nmnat1 is a potent inhibitor of axonal degeneration in models of acute axonal injury. Hyperphosphorylation and aggregation of the microtubule‐associated protein Tau are associated with neurodegeneration in Alzheimer's Disease and other disorders. Previous studies have demonstrated that other Nmnat isoforms can act both as axonoprotective agents and have protein chaperone function, exerting protective effects in drosophila and mouse models of tauopathy. Nmnat1 targeted to the cytoplasm (cytNmnat1) is neuroprotective in a mouse model of neonatal hypoxia‐ischemia, but the effect of cytNmnat1 on tauopathy remains unknown.MethodsWe examined the impact of overexpression of cytNmnat1 on tau pathology, neurodegeneration, and brain functional connectivity in the P301S mouse model of chronic tauopathy.ResultsOverexpression of cytNmnat1 preserved cortical neuron functional connectivity in P301S mice in vivo. However, whereas Nmnat1 overexpression decreased the accumulation of detergent‐insoluble tau aggregates in the cerebral cortex, it exerted no effect on immunohistochemical evidence of pathologic tau phosphorylation and misfolding, hippocampal atrophy, or inflammatory markers in P301S mice.InterpretationOur results demonstrate that cytNmnat1 partially preserves neuronal function and decreases biochemically insoluble tau in a mouse model of chronic tauopathy without preventing tau phosphorylation, formation of soluble aggregates, or tau‐induced inflammation and atrophy. Nmnat1 might thus represent a therapeutic target for tauopathies.

show abstract

Altered expression of neurofilament 200 and amyloid-β peptide (1–40) in a rat model of chronic cerebral hypoperfusion

et al. 2014

View full text Add to dashboard Cite

Chronic cerebral hypoperfusion (CCH) is damaging to white matter in the brain. So far few studies have investigated long-term axonal damage following CCH. The aim of this study was to investigate the involvement of neurofilament 200 (NF200) and amyloid-β (1-40) [Aβ (1-40)] in the pathological mechanism for neuronal damage, and to quantify changes in their expression over time in a rat model of CCH. A rat model of CCH was established using partial bilateral ligation of the common carotid arteries. The extent of stenosis was verified by measuring the changes in cerebral blood flow after surgery. Histology was used to assess hippocampal neuronal pathology, and immunohistochemistry was used to quantify the expression of NF200 and Aβ (1-40) at 2, 4, and 12 weeks after surgery. The cerebral blood flow reduced to 33.89 ± 5.48 % at 2 weeks, 36.83 ± 4.63 % at 4 weeks and 51.44 ± 4.90 % at 12 weeks. Immunofluorescence staining of neuronal perikarya sections revealed a marked decrease in the population of surviving pyramidal cells in the hippocampal CA1 region, a significant up-regulation in the expression of Aβ (1-40), and a significant reduction in the expression of NF200 following CCH surgery. Moreover, this trend was increasingly obvious over time. Our data demonstrate that CCH leads to axonal damage over time. We also confirmed that the expression of Aβ (1-40) and NF200 may be useful biomarkers of axonal damage following CCH.

show abstract

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

Cited by 34 publications

References 41 publications

Deciphering the mechanism underlying late-onset Alzheimer disease

Deciphering the mechanism underlying late-onset Alzheimer disease

Nmnat1 protects neuronal function without altering phospho‐tau pathology in a mouse model of tauopathy

Altered expression of neurofilament 200 and amyloid-β peptide (1–40) in a rat model of chronic cerebral hypoperfusion

Contact Info

Product

Resources

About