Accumulation of carboxy-terminal fragments of APP increases phosphodiesterase 8B

Kametani, Fuyuki; Haga, Shukoh

doi:10.1016/j.neurobiolaging.2014.09.029

Cited by 19 publications

(14 citation statements)

References 36 publications

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“…6 ) 10 , 11 . The 3xTg-AD-H mice exhibit mainly intracellular Aβ accumulation before 12 months of age, accompanied by increased levels of intracellular APP sub-products, as well as Tau pathologies such as intracellular NFT and cognitive impairment, accompanied by astrocytosis but not microgliosis (Supplementary Figs S8 , S9 and S10 ) 9 , 17 , 34 , 35 . Differences in both the gene expression profiles and pathologies observed between the two AD mouse models strongly suggest that extracellular but not intracellular Aβ induces gliosis, namely neuroinflammatory responses, similar to what is observed in human AD temporal cortex.…”

Section: Discussionmentioning

confidence: 99%

“…2b ), but these genes were not altered in the App NL-G-F/NL-G-F cortex. In contrast, intracellular accumulation of Aβ and other APP sub-products, and/or Tau pathologies, are likely related to the neuronal metabolic and synaptic dysfunctions, as evident in the hippocampus of both human AD and 3xTg-AD-H brains 9 , 18 .…”

Section: Discussionmentioning

confidence: 99%

“…Transgenic mouse models overexpress genetically modified Aβ precursor protein (APP), presenilin (PSEN) and/or the microtubule-associated protein tau (MAPT), to induce accumulation of Aβ or neuronal dysfunction. However, these transgenic mouse models develop AD-like pathologies at different ages and to different extents due to expression levels of AD-related proteins that are dependent on promoters used in transgene constructs, as well as copy number of transgenes and inserted regions 7 – 9 . To more accurately reproduce AD pathologies, App knock-in mouse models that carry pathogenic mutation(s) in App and/or Psen1 genes have been established.…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Comparative profiling of cortical gene expression in Alzheimer’s disease patients and mouse models demonstrates a link between amyloidosis and neuroinflammation

Castillo

Leon

Mazzei

et al. 2017

Sci Rep

149

119

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Alzheimer’s disease (AD) is the most common form of dementia, characterized by accumulation of amyloid β (Aβ) and neurofibrillary tangles. Oxidative stress and inflammation are considered to play an important role in the development and progression of AD. However, the extent to which these events contribute to the Aβ pathologies remains unclear. We performed inter-species comparative gene expression profiling between AD patient brains and the App NL-G-F/NL-G-F and 3xTg-AD-H mouse models. Genes commonly altered in App NL-G-F/NL-G-F and human AD cortices correlated with the inflammatory response or immunological disease. Among them, expression of AD-related genes (C4a/C4b, Cd74, Ctss, Gfap, Nfe2l2, Phyhd1, S100b, Tf, Tgfbr2, and Vim) was increased in the App NL-G-F/NL-G-F cortex as Aβ amyloidosis progressed with exacerbated gliosis, while genes commonly altered in the 3xTg-AD-H and human AD cortices correlated with neurological disease. The App NL-G-F/NL-G-F cortex also had altered expression of genes (Abi3, Apoe, Bin2, Cd33, Ctsc, Dock2, Fcer1g, Frmd6, Hck, Inpp5D, Ly86, Plcg2, Trem2, Tyrobp) defined as risk factors for AD by genome-wide association study or identified as genetic nodes in late-onset AD. These results suggest a strong correlation between cortical Aβ amyloidosis and the neuroinflammatory response and provide a better understanding of the involvement of gender effects in the development of AD.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Comparative profiling of cortical gene expression in Alzheimer’s disease patients and mouse models demonstrates a link between amyloidosis and neuroinflammation

Castillo

Leon

Mazzei

et al. 2017

Sci Rep

149

119

View full text Add to dashboard Cite

show abstract

“…The major products of this APP metabolic pathway are sAPPα, C83, p3, and APP intracellular domain (AICD), and Aβ is a minor product. Moreover, AICD is rapidly degraded (Cupers et al, 2001 ; Kopan and Ilagan, 2004 ; Kametani and Haga, 2015 ), suggesting that APP C-terminal fragments (C83, C99, and AICD) may be toxic and need to be removed (Kametani, 2008 ; Robakis and Georgakopoulos, 2014 ). Thus, when considering the effects of familial AD mutations, the effects on all the major products of APP metabolism should be considered.…”

Section: Reconsideration Of App and Presenilin (Ps) Mutations In Famimentioning

confidence: 99%

“…Therefore, the major products in this APP metabolic pathway are sAPPα, C83, p3, and AICD, and Aβ is a minor product. AICD is rapidly degraded (Cupers et al, 2001 ; Kopan and Ilagan, 2004 ; Kametani and Haga, 2015 ). Thus, mutations found in familial AD, especially presenilin mutations, may affect the formation and processing of a variety of products.…”

Section: Introductionmentioning

confidence: 99%

Reconsideration of Amyloid Hypothesis and Tau Hypothesis in Alzheimer's Disease

2018

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The so-called amyloid hypothesis, that the accumulation and deposition of oligomeric or fibrillar amyloid β (Aβ) peptide is the primary cause of Alzheimer's disease (AD), has been the mainstream concept underlying AD research for over 20 years. However, all attempts to develop Aβ-targeting drugs to treat AD have ended in failure. Here, we review recent findings indicating that the main factor underlying the development and progression of AD is tau, not Aβ, and we describe the deficiencies of the amyloid hypothesis that have supported the emergence of this idea.

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The pathological and biochemical identification of possible seed‐lesions of transmitted transthyretin amyloidosis after domino liver transplantation

Yoshinaga

Yazaki

Sekijima

et al. 2016

The Journal of Pathology CR

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The most serious issue in domino liver transplantation (DLT) using liver grafts from patients with transthyretin (TTR)‐related familial amyloid polyneuropathy (FAP) is the development of iatrogenic transmitted amyloidosis (de novo amyloidosis) in DLT‐recipients. However, little is known regarding the mechanisms of the initial stage of amyloid formation in these recipients. We detected initial lesions (possible seed‐lesions) of this iatrogenic amyloidosis in two recipients following liver grafting from FAP patients. Patient 1 underwent DLT at age 65 from an FAP patient with a Val30Met TTR variant and patient 2 received DLT from an FAP patient with a Val30Leu TTR variant at age 32. Patient 2 was started on diflunisal administration from 4 years after DLT. While neither patient had symptoms of FAP, small amyloid deposits were detected on the gastroduodenal mucosae 14 months and 12 years after DLT in patient 1 and patient 2, respectively. The amyloid was analyzed using a laser microdissection system and tandem mass spectrometry. Biochemical analysis indicated that the amyloid was composed mostly of variant TTR produced from the transplanted liver in both patients. In patient 1, wild‐type TTR amyloid was detectable in the duodenal mucosa obtained 2 years after DLT. This is the first study to successfully capture the pathological and biochemical features of initial‐stage amyloid lesions in DLT recipients. The findings clearly indicate that amyloid deposition can start by deposition of variant TTR followed by deposition of wild‐type TTR, and blocking of amyloid seed formation from variant TTR may be a key to prevent or delay the development of DLT‐associated amyloidosis.

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Accumulation of carboxy-terminal fragments of APP increases phosphodiesterase 8B

Cited by 19 publications

References 36 publications

Comparative profiling of cortical gene expression in Alzheimer’s disease patients and mouse models demonstrates a link between amyloidosis and neuroinflammation

Comparative profiling of cortical gene expression in Alzheimer’s disease patients and mouse models demonstrates a link between amyloidosis and neuroinflammation

Reconsideration of Amyloid Hypothesis and Tau Hypothesis in Alzheimer's Disease

The pathological and biochemical identification of possible seed‐lesions of transmitted transthyretin amyloidosis after domino liver transplantation

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