β-amyloid controls altered Reelin expression and processing in Alzheimer's disease

Botella-López, Arancha; Cuchillo-Ibáñez, Inmaculada; Cotrufo, Tiziana; Mok, Su San; Li, Qiao‐Xin; Barquero, María Sagrario; Dierssen, Mara; Soriano, Eduardo; Sáez‐Valero, Javier

doi:10.1016/j.nbd.2009.12.006

Cited by 54 publications

(64 citation statements)

References 62 publications

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“…A reciprocal effect is also conceivable, with A␤ peptides promoting Reelin aggregation. Support for this hypothesis has been recently provided by Botella-Ló pez et al (2010), demonstrating that amyloid-␤ peptides can alter Reelin processing and glycosylation, critical modifications demonstrated to be required for proper Reelin-mediated signaling (Lambert de Rouvroit et al, 1999;Koch et al, 2002;Jossin et al, 2007) and potentially involved in abnormal oligomerization and aggregation of Reelin (Utsunomiya-Tate et al, 2000;Kubo et al, 2002;Yasui et al, 2007).…”

Section: Discussionmentioning

confidence: 93%

Reduced Reelin Expression Accelerates Amyloid- Plaque Formation and Tau Pathology in Transgenic Alzheimer's Disease Mice

Kocherhans¹,

Madhusudan²,

Doehner³

et al. 2010

Journal of Neuroscience

111

102

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In addition to the fundamental role of the extracellular glycoprotein Reelin in neuronal development and adult synaptic plasticity, alterations in Reelin-mediated signaling have been suggested to contribute to neuronal dysfunction associated with Alzheimer's disease (AD). In vitro data revealed a biochemical link between Reelin-mediated signaling, Tau phosphorylation, and amyloid precursor protein (APP) processing. To directly address the role of Reelin in amyloid-␤ plaque and Tau pathology in vivo, we crossed heterozygous Reelin knock-out mice (reeler) with transgenic AD mice to investigate the temporal and spatial AD-like neuropathology. We demonstrate that a reduction in Reelin expression results in enhanced amyloidogenic APP processing, as indicated by the precocious production of amyloid-␤ peptides, the significant increase in number and size of amyloid-␤ plaques, as well as age-related aggravation of plaque pathology in double mutant compared with single AD mutant mice of both sexes. Numerous amyloid-␤ plaques accumulate in the hippocampal formation and neocortex of double mutants, precisely in layers with strongest Reelin expression and highest accumulation of Reelin plaques in aged wild-type mice. Moreover, concentric accumulations of phosphorylated Tau-positive neurons around amyloid-␤ plaques were evident in 15-month-old double versus single mutant mice. Silver stainings indicated the presence of neurofibrillary tangles, selectively associated with amyloid-␤ plaques and dystrophic neurites in the entorhinal cortex and hippocampus. Our findings suggest that age-related Reelin aggregation and concomitant reduction in Reelin-mediated signaling play a proximal role in synaptic dysfunction associated with amyloid-␤ deposition, sufficient to enhance Tau phosphorylation and tangle formation in the hippocampal formation in aged Reelin-deficient transgenic AD mice.

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Section: Discussionmentioning

confidence: 93%

Reduced Reelin Expression Accelerates Amyloid- Plaque Formation and Tau Pathology in Transgenic Alzheimer's Disease Mice

Kocherhans¹,

Madhusudan²,

Doehner³

et al. 2010

Journal of Neuroscience

111

102

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“…Functional links between the Reelin pathway and AD include molecular cross-talk between the Reelin signalling pathway and both APP processing and Tau phosphorylation 15,16 , altered expression of Reelin in AD brains [18][19][20][21][22] , the presence of Reelin in amyloid plaques 14 and genetic RLN variants linked to AD 23,24 . However, the contribution of Reelin to AD pathogenesis and progression is not yet understood 36 .…”

Section: Discussionmentioning

confidence: 99%

“…In relation to AD pathology, Reelin is present in amyloid plaques 14 , controls APP processing 15 , reduces Tau phosphorylation by inhibiting GSK3b 16 and counteracts Ab-induced synaptic dysfunction 17 . In addition, AD brain samples show altered levels of Reelin [18][19][20][21][22] , and the RELN gene bears polymorphic variants associated with normal cognitive function in AD pathology 23,24 . Finally, the reduction of Reelin in an AD mouse model accelerates the onset of plaque formation and Tau pathology 25 .…”

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confidence: 99%

Reelin delays amyloid-beta fibril formation and rescues cognitive deficits in a model of Alzheimer’s disease

et al. 2014

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Reelin is an extracellular matrix protein that is crucial for neural development and adult brain plasticity. While the Reelin signalling cascade has been reported to be associated with Alzheimer's disease (AD), the role of Reelin in this pathology is not understood. Here we use an in vitro approach to show that Reelin interacts with amyloid-b (Ab 42 ) soluble species, delays Ab 42 fibril formation and is recruited into amyloid fibrils. Furthermore, Reelin protects against both the neuronal death and dendritic spine loss induced by Ab 42 oligomers. In mice carrying the APP Swe/Ind mutation (J20 mice), Reelin overexpression delays amyloid plaque formation and rescues the recognition memory deficits. Our results indicate that by interacting with Ab 42 soluble species, delaying Ab plaque formation, protecting against neuronal death and dendritic spine loss and preventing AD cognitive deficits, the Reelin pathway deserves consideration as a therapeutic target for the treatment of AD pathogenesis.

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“…The glycosylation of reelin has been investigated with lectin-binding studies, which have shown a reduced extent of binding to Con A in CSF from AD patients [87]. Similarly, the fraction of reelin that does not bind to Con A is decreased in the frontal cortex from AD patients, and, as for AChE, Ab appears to alter the glycosylation of reelin [88].…”

Section: Other Proteins Of Relevance To Admentioning

confidence: 99%

The role of protein glycosylation in Alzheimer disease

2013

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Glycosylation is one of the most common, and the most complex, forms of post-translational modification of proteins. This review serves to highlight the role of protein glycosylation in Alzheimer disease (AD), a topic that has not been thoroughly investigated, although glycosylation defects have been observed in AD patients. The major pathological hallmarks in AD are neurofibrillary tangles and amyloid plaques. Neurofibrillary tangles are composed of phosphorylated tau, and the plaques are composed of amyloid b-peptide (Ab), which is generated from amyloid precursor protein (APP). Defects in glycosylation of APP, tau and other proteins have been reported in AD. Another interesting observation is that the two proteases required for the generation of amyloid b-peptide (Ab), i.e. c-secretase and b-secretase, also have roles in protein glycosylation. For instance, c-secretase and b-secretase affect the extent of complex N-glycosylation and sialylation of APP, respectively. These processes may be important in AD pathogenesis, as proper intracellular sorting, processing and export of APP are affected by how it is glycosylated. Furthermore, lack of one of the key components of c-secretase, presenilin, leads to defective glycosylation of many additional proteins that are related to AD pathogenesis and/or neuronal function, including nicastrin, reelin, butyrylcholinesterase, cholinesterase, neural cell adhesion molecule, v-ATPase, and tyrosine-related kinase B. Improved understanding of the effects of AD on protein glycosylation, and vice versa, may therefore be important for improving the diagnosis and treatment of AD patients.

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β-amyloid controls altered Reelin expression and processing in Alzheimer's disease

Cited by 54 publications

References 62 publications

Reduced Reelin Expression Accelerates Amyloid- Plaque Formation and Tau Pathology in Transgenic Alzheimer's Disease Mice

Reduced Reelin Expression Accelerates Amyloid- Plaque Formation and Tau Pathology in Transgenic Alzheimer's Disease Mice

Reelin delays amyloid-beta fibril formation and rescues cognitive deficits in a model of Alzheimer’s disease

The role of protein glycosylation in Alzheimer disease

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