Nonfibrillar diffuse amyloid deposition due to a gamma42-secretase site mutation points to an essential role for N-truncated Abeta42 in Alzheimer's disease

Kumar‐Singh, Samir; Jonghe, Chris De; Cruts, Marc; Kleinert, R.; Wang, Rong; Mercken, Marc; Strooper, Bart De; Vanderstichele, Hugo; Löfgren, A.; Vanderhoeven, Inge; Backhovens, Hubert; Vanmechelen, Eugeen; Kroisel, Peter M.; Broeckhoven, Christine Van

doi:10.1093/hmg/9.18.2589

Cited by 148 publications

(104 citation statements)

References 48 publications

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“…Age-related CAA has been noted in a variety of vertebrate species (Walker 1997;Kumar-Singh et al 2000;Brellou et al 2005;Elfenbein et al 2007). The lack of appropriate animal models is an obstacle to understanding CAA (Revesz et al 2003;Elfenbein et al 2007), but presently there are a few well-established, natural models of sporadic CAA.…”

Section: Discussionmentioning

confidence: 99%

Histological and immunohistochemical characteristics of cerebral amyloid angiopathy in elderly dogs

Nešić

Kukolj

Marinković

et al. 2016

Veterinary Quarterly

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Background: Cerebral amyloid angiopathy (CAA) is a disorder characterized by amyloid deposition in the wall of cerebral blood vessels. The deposits of amyloid occur frequently in the blood vessels of the frontal, parietal and occipital cortex. Objective: To examine the characteristics of CAA classified according to the Vonsattel scale in elderly dogs histologically and immunohistochemically as well as the semi-quantitative evaluation of the amyloid deposits in the different segments of the brain. Animals and methods: The brains of 36 dogs of different breeds and sexes, which had been routinely necropsied, were used and divided into two groups: dogs from 1 to 5 and 10 to 18 years old. The tissue sections were stained by hematoxylin-eosin, Congo red and immunohistochemically. Results: Amyloid was accumulated in the wall of cerebral blood vessels in 70% of dogs over the age of 10 years predominantly in the frontal cortex. CAA was demonstrated in elderly dogs as follows: in the frontal cortex (n D 19 or 63%), the parietal cortex (n D 12 or 40%), the hippocampus (40%) and the cerebellum (n D 5 or 17%). The deposits of amyloid in the wall of blood vessels detected by Congo red staining were also Ab1-14 and Ab1-42 immunohistochemically positive. Most commonly, the amyloid deposits affected a moderate number of blood vessels. The accumulation of amyloid was immunohistochemically revealed in the blood vessel walls as well as in the senile plaques and neurons. Conclusion: The amount of amyloid in the arterial walls increased with age in dogs, whereas the amyloid accumulated in plaques was Congo red negative.

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Section: Discussionmentioning

confidence: 99%

Histological and immunohistochemical characteristics of cerebral amyloid angiopathy in elderly dogs

Nešić

Kukolj

Marinković

et al. 2016

Veterinary Quarterly

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“…Heterozygous APP mutations affecting codons from 714 to 717 alter g-secretase cleavage causing an increase of the b-amyloid (Ab)42/Ab40 ratio. 9,10 In AD families, Ab42 elevated levels have been reported among symptomatic carriers of presenilin mutations, 11 and Ab42 and Ab42/Ab40 ratio levels were higher in unaffected familial AD mutation carriers compared with the unaffected individuals without mutation belonging to the same AD families. 12 First-degree relatives of patients with late-onset AD without any known mutations have also been found to have an increase of plasma Ab42.…”

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confidence: 96%

Homozygous carriers of APP A713T mutation in an autosomal dominant Alzheimer disease family

et al. 2015

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Objective: To report, for the first time, a large autosomal dominant Alzheimer disease (AD) family in which the APP A713T mutation is present in the homozygous and heterozygous state. To date, the mutation has been reported as dominant, and in the heterozygous state associated with familial AD and cerebrovascular lesions. Methods:The family described here has been genealogically reconstructed over 6 generations dating back to the 19th century. Plasma b-amyloid peptide was measured. Sequencing of causative AD genes was performed.Results: Twenty-one individuals, all but 1 born from 2 consanguineous unions, were studied: 8 were described as affected through history, 5 were studied clinically and genetically, and 8 were asymptomatic at-risk subjects. The A713T mutation was detected in the homozygous state in 3 patients and in the heterozygous state in 8 subjects (6 asymptomatic and 2 affected).Conclusions: Our findings, also supported by the b-amyloid plasma assay, confirm (1) the pathogenic role of the APP A713T mutation, (2) the specific phenotype (AD with cerebrovascular lesions) associated with this mutation, and (3) the large span of age at onset, not influenced by APOE, TOMM40, and TREM2 genes. No substantial differences concerning clinical phenotype were evidenced between heterozygous and homozygous patients, in line with the classic definition of dominance. Therefore, in this study, AD followed the classic definition of a dominant disease, contrary to that reported in a previously described AD family with recessive APP mutation. This confirms that genetic AD may be considered a disease with dominant and recessive traits of inheritance. Neurology ® 2015;84:2266-2273 GLOSSARY Ab 5 b-amyloid; AD 5 Alzheimer disease; ADL 5 activities of daily living; AMC 5 affected mutation carrier; APP 5 amyloid precursor protein; ASMC 5 asymptomatic mutation carrier; CVL 5 cerebrovascular lesion; FDG 5 fluorodeoxyglucose; HIS 5 Hachinski Ischemic Score; IADL 5 instrumental activities of daily living; MMSE 5 Mini-Mental State Examination; NMC 5 non-mutation carrier; PolyPhen-2 5 Polymorphism Phenotyping 2; PSEN1 5 presenilin 1; PSEN2 5 presenilin 2; SIFT 5 sorting intolerant from tolerant.

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“…Amino-acid substitutions in the g-site lead to high Ab42/40 ratios and are characterized by the most prominent and earliest phenotypes of FAD 17 .…”

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confidence: 99%

Alzheimer’s disease mutations in APP but not γ-secretase modulators affect epsilon-cleavage-dependent AICD production

et al. 2013

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Pathological amino-acid substitutions in the amyloid precursor protein (APP) and chemical g-secretase modulators affect the processing of APP by the g-secretase complex and the production of the amyloid-beta peptide Ab42, the accumulation of which is considered causative of Alzheimer's disease. Here we demonstrate that mutations in the transmembrane domain of APP causing aggressive early-onset familial Alzheimer's disease affect both g-and e-cleavage sites, by raising the Ab42/40 ratio and inhibiting the production of AICD50-99, one of the two physiological APP intracellular domains (ICDs). This is in sharp contrast to g-secretase modulators, which shift Ab42 production towards the shorter Ab38, but unequivocally spare the e-site and APP-and Notch-ICDs production. Molecular simulations suggest that familial Alzheimer's disease mutations modulate the flexibility of the APP transmembrane domain and the presentation of its g-site, modifying at the same time, the solvation of the e-site.

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Nonfibrillar diffuse amyloid deposition due to a gamma42-secretase site mutation points to an essential role for N-truncated Abeta42 in Alzheimer's disease

Cited by 148 publications

References 48 publications

Histological and immunohistochemical characteristics of cerebral amyloid angiopathy in elderly dogs

Histological and immunohistochemical characteristics of cerebral amyloid angiopathy in elderly dogs

Homozygous carriers of APP A713T mutation in an autosomal dominant Alzheimer disease family

Alzheimer’s disease mutations in APP but not γ-secretase modulators affect epsilon-cleavage-dependent AICD production

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