Transgenic mice expressing APP-C100 in the brain

Neve, Rachael L.; Boyce, Frederick M.; McPhie, Donna L.; Greenan, Jane; Oster-Granite, Mary Lou

doi:10.1016/0197-4580(95)02074-8

Cited by 41 publications

(25 citation statements)

References 29 publications

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“…A number of studies have compared APP transcript levels in normal and AD brains. However, findings to date have been contradictory with data reporting a selective reduction in APP 695 (8, 29 -31), an increase in APP 695 (65,70), an increase in the ratio of APP 770 / APP 695 (25,27,34,35) or APP 751 /APP 695 (32,36,38), and no change in the relative message levels of different isoforms (57,58,(75)(76)(77)(78)(79)(80). Message levels for APP 751 and APP 770 are also reported to be increased in fibroblasts carrying the FAD Swedish APP 670/671 mutation and in normal fibroblasts in response to stress (81).…”

Section: Table IVmentioning

confidence: 44%

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Relative Increase in Alzheimer's Disease of Soluble Forms of Cerebral Aβ Amyloid Protein Precursor Containing the Kunitz Protease Inhibitory Domain

Moir¹,

Lynch²,

Bush³

et al. 1998

Journal of Biological Chemistry

101

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Although a number of studies have examined amyloid precursor protein (APP) mRNA levels in Alzheimer's disease (AD), no clear consensus has emerged as to whether the levels of transcripts for isoforms containing a Kunitz protease inhibitory (KPI)-encoded region are increased or decreased in AD. Here we compare AD and control brain for the relative amounts of APP protein containing KPI to APP protein lacking this domain. APP protein was purified from the soluble subcellular fraction and Triton X-100 membrane pellet extract of one hemisphere of AD (n ‫؍‬ 10), normal (n ‫؍‬ 7), and neurological control (n ‫؍‬ 5) brains. The amount of KPI-containing APP in the purified protein samples was determined using two independent assay methods. The pathological hallmark of Alzheimer's disease (AD) 1 is the deposition of amyloid as cerebrovascular, diffuse and neuritic plaques (within the brain extracellular space), and neurofibrillary tangles (within neurons). The principal component of extracellular amyloid is a 4-kDa peptide, the A␤ protein (1, 2) (also called the ␤A4 protein). The A␤ peptide is not expressed as a functional protein entity (3) but is released by the processing of a much larger transmembrane protein, the amyloid protein precursor (APP). The pathogenesis of AD is thought to involve the disregulated expression or abnormal processing of APP.APP is encoded by a single 18-exon gene on chromosome 21 (4 -6). Exons 7, 8, and 15 of the APP gene can be alternatively spliced to produce multiple isoforms. In brain the predominant isoform transcripts demonstrated to date are APP 695 , APP 751 , and APP 770 (7-9). These transcripts code for species containing 695, 751, and 770 amino acids, respectively. The isoforms APP 751 and APP 770 both contain a Kunitz protease inhibitory (KPI) motif that APP 695 lacks. APP 770 contains an additional OX.2 domain (7, 10). The secreted form of APP 751 is identical to protease nexin II, a plasma serine protease inhibitor (11). In addition to KPI and OX.2 domains several other structural features have been identified on APP, including binding domains for heparin (12), zinc (13,14) and copper (15), and N-linked carbohydrate attachment sites (10).Normal catabolism of APP involves proteolytic cleavage of full-length membrane-associated forms within the extracellular domain of the A␤ region and release of soluble COOHterminal truncated species (sAPP) (16,17). The proteases that release sAPP have yet to be identified but have been named the ␣-and ␤-secretases. The ␣-secretase cleaves within the A␤ sequence of APP and its products are non-amyloidogenic. The ␤-secretase cleavage site is the NH 2 terminus of the A␤ domain. The proteolytic activities that release intact A␤ from the transmembrane domain of APP (COOH terminus of A␤) have been designated ␥-secretases. The catabolic pathway for A␤ generation is unclear but probably involves internalization of full-length APP from the cell surface and degradation in endosomal-lysosomal complexes (18 -20). In cultured hamster cells one route for A␤ p...

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Section: Table IVmentioning

confidence: 44%

“…brain where they are a major neuronal APP mRNA species (25,26). The KPI ϩ isoforms APP 751 and APP 770 are expressed in both the central nervous system and in peripheral tissues.…”

mentioning

confidence: 99%

Relative Increase in Alzheimer's Disease of Soluble Forms of Cerebral Aβ Amyloid Protein Precursor Containing the Kunitz Protease Inhibitory Domain

Moir¹,

Lynch²,

Bush³

et al. 1998

Journal of Biological Chemistry

101

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show abstract

“…In fact, increases in C99 were already shown to contribute to other aspects of the pathogenesis of the disease (Saito et al , 2011; Lauritzen et al , 2012), including endosomal dysfunction (Jiang et al , 2010), hippocampal degeneration (Lauritzen et al , 2012), and altered Tau proteostasis (Moore et al , 2015). In addition, elevations in C99 are toxic to neurons (Neve et al , 1996), correlating with symptoms of the disease (Rockenstein et al , 2005; Tamayev et al , 2012). Importantly, we note that although much of our data were obtained using FAD models and cells from FAD patients containing mutations in presenilins, alterations in γ‐secretase activity and increased levels of C99 have been detected in sporadic AD patients as well (Fukumoto et al , 2002; Yang et al , 2003; Li et al , 2004; Pera et al , 2013).…”

Section: Discussionmentioning

confidence: 99%

Increased localization of APP‐C99 in mitochondria‐associated ER membranes causes mitochondrial dysfunction in Alzheimer disease

et al. 2017

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In the amyloidogenic pathway associated with Alzheimer disease (AD), the amyloid precursor protein (APP) is cleaved by β‐secretase to generate a 99‐aa C‐terminal fragment (C99) that is then cleaved by γ‐secretase to generate the β‐amyloid (Aβ) found in senile plaques. In previous reports, we and others have shown that γ‐secretase activity is enriched in mitochondria‐associated endoplasmic reticulum (ER) membranes (MAM) and that ER–mitochondrial connectivity and MAM function are upregulated in AD. We now show that C99, in addition to its localization in endosomes, can also be found in MAM, where it is normally processed rapidly by γ‐secretase. In cell models of AD, however, the concentration of unprocessed C99 increases in MAM regions, resulting in elevated sphingolipid turnover and an altered lipid composition of both MAM and mitochondrial membranes. In turn, this change in mitochondrial membrane composition interferes with the proper assembly and activity of mitochondrial respiratory supercomplexes, thereby likely contributing to the bioenergetic defects characteristic of AD.

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“…The mutation disrupts the gene's production of dystrophin, a protein product. Normally, dystrophin localizes to a glycoprotein complex in the muscle cell membrane and provides structural support (Neve et al, 1996). Without it, muscle cells subject to the force of contraction of normal muscle use develop tears in the cell membrane leading to cellular breakdown and cell death.…”

Section: Introductionmentioning

confidence: 99%

Selective deficits in verbal working memory associated with a known genetic etiology: The neuropsychological profile of Duchenne muscular dystrophy

Hinton

Vivo

Nereo

et al. 2001

J Int Neuropsychol Soc

103

100

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Forty-one boys diagnosed with Duchenne muscular dystrophy (DMD) were each compared to an unaffected sibling on a battery of neuropsychological tests. Verbal, visuospatial, attention/memory, abstract thinking, and academic achievement skills were tested. Results indicated the boys with DMD performed similarly to their siblings on the majority of measures, indicating intact verbal, visuospatial, long-term memory, and abstract skills. However, the DMD group did significantly more poorly than their siblings on specific measures of story recall, digit span, and auditory comprehension, as well as in all areas of academic achievement (reading, writing, and math). This profile indicates that verbal working memory skills are selectively impaired in DMD, and that that likely contributes to limited academic achievement. The association between the known impact of the genetic mutation on the development of the central nervous system and boys' cognitive profile is discussed.

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Transgenic mice expressing APP-C100 in the brain

Cited by 41 publications

References 29 publications

Relative Increase in Alzheimer's Disease of Soluble Forms of Cerebral Aβ Amyloid Protein Precursor Containing the Kunitz Protease Inhibitory Domain

Relative Increase in Alzheimer's Disease of Soluble Forms of Cerebral Aβ Amyloid Protein Precursor Containing the Kunitz Protease Inhibitory Domain

Increased localization of APP‐C99 in mitochondria‐associated ER membranes causes mitochondrial dysfunction in Alzheimer disease

Selective deficits in verbal working memory associated with a known genetic etiology: The neuropsychological profile of Duchenne muscular dystrophy

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