Acetylcholinesterase Is Increased in the Brains of Transgenic Mice Expressing the C‐Terminal Fragment (CT100) of the β‐Amyloid Protein Precursor of Alzheimer's Disease

Sberna, Gian; Sáez‐Valero, Javier; Li, Qiao‐Xin; Czech, Christian; Beyreuther, Konrad; Masters, Colin L.; McLean, Catriona; Small, David H.

doi:10.1046/j.1471-4159.1998.71020723.x

Cited by 97 publications

(65 citation statements)

References 30 publications

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“…4C). AChE exhibits complex structural polymorphism (39) with a molecular form pattern which is altered in AD (18,66,70). Accordingly, we found that the major G 4 ).…”

Section: Resultsmentioning

confidence: 79%

“…Despite an overall decrease in the AD brain, the activity of AChE is increased around the amyloid plaques (42,78). This may be a direct consequence of amyloid deposition, since A␤ peptides influence AChE levels in cell cultures (25,69) and in the brains of transgenic mice that produce human A␤ (70). Conversely, AChE may play a role in A␤ fibrillogenesis (27,60).…”

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confidence: 99%

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Presenilin 1 Interacts with Acetylcholinesterase and Alters Its Enzymatic Activity and Glycosylation

Silveyra

Evin

Montenegro

et al. 2008

Molecular and Cellular Biology

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Presenilin 1 (PS1) plays a critical role in the ␥-secretase processing of the amyloid precursor protein to generate the ␤-amyloid peptide, which accumulates in plaques in the pathogenesis of Alzheimer's disease (AD). Mutations in PS1 cause early onset AD, and proteins that interact with PS1 are of major functional importance. We report here the coimmunoprecipitation of PS1 and acetylcholinesterase (AChE), an enzyme associated with amyloid plaques. Binding occurs through PS1 N-terminal fragment independent of the peripheral binding site of AChE. Subcellular colocalization of PS1 and AChE in cultured cells and coexpression patterns of PS1 and AChE in brain sections from controls and subjects with sporadic or familial AD indicated that PS1 and AChE are located in the same intracellular compartments, including the perinuclear compartments. A PS1-A246E pathogenic mutation expressed in transgenic mice leads to decreased AChE activity and alteration of AChE glycosylation and the peripheral binding site, which may reflect a shift in protein conformation and disturbed AChE maturation. In both the transgenic mice and humans, mutant PS1 impairs coimmunoprecipitation with AChE. The results indicate that PS1 can interact with AChE and influence its expression, supporting the notion of cholinergic-amyloid interrelationships.Alzheimer's disease (AD) is characterized by the presence of large numbers of amyloid plaques and neurofibrillary tangles in the brain (56). The major constituent of the amyloid plaques is the ␤-amyloid protein (A␤), a polypeptide generated by processing of a much larger amyloid precursor protein (APP) through the successive action of two proteolytic enzymes, ␤-secretase and ␥-secretase (71). ␥-Secretase is a membrane protease complex comprising presenilin 1 (PS1) as a catalytic subunit (76). The importance of PS was first highlighted by genetic studies of AD. Families bearing mutations in the PS1 gene, or in the highly homologous presenilin 2 (PS2) gene, invariably develop an aggressive form of early-onset AD with an accelerated rate of A␤ deposition (75).The accumulation of A␤ peptide in the brain is thought to be an important step in the pathogenesis of AD, leading to a number of neurodegenerative changes (19). In particular, there is a decrease in cholinergic activity in the basal forebrain of AD patients, which affects activity of the acetylcholinesynthesizing enzyme, choline acetyltransferase, as well as the acetylcholine-hydrolyzing enzyme, acetylcholinesterase (AChE) (13, 53). The altered expression of AChE in the AD-affected brain (AD brain) is of particular interest. Despite an overall decrease in the AD brain, the activity of AChE is increased around the amyloid plaques (42,78). This may be a direct consequence of amyloid deposition, since A␤ peptides influence AChE levels in cell cultures (25,69) and in the brains of transgenic mice that produce human A␤ (70). Conversely, AChE may play a role in A␤ fibrillogenesis (27,60). Finally, several investigations have argued for a strict interrelation b...

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“…4C). AChE exhibits complex structural polymorphism (39) with a molecular form pattern which is altered in AD (18,66,70). Accordingly, we found that the major G 4 ).…”

Section: Resultsmentioning

confidence: 79%

mentioning

confidence: 99%

Presenilin 1 Interacts with Acetylcholinesterase and Alters Its Enzymatic Activity and Glycosylation

Silveyra

Evin

Montenegro

et al. 2008

Molecular and Cellular Biology

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“…TghCTF99/B6 mice express hCTF99(V717F), thus it is possible that histological and behavioral changes observed in Tg-hCTF99/ B6 mice are due to an as-yet-unidentified toxic effect of hCTF99(V717F). Among the previously generated transgenic mouse lines expressing CTFs described in Introduction, three lines had been designed to express mutant forms of CTFs, C100(V -I) (Araki et al, 1994), C100(V -F) (Sberna et al, 1998), and C99(I -F) (Rutten et al, 2003), although these transgenic lines do not show any obvious AD-like pathogenesis. In particular, transgenic mice expressing C100(V -F) (Sberna et al, 1998) carry a mutation essentially identical to that of Tg-hCTF99/B6 mice but showed no clear phenotype.…”

Section: The Roles Of Bctf99 In Ad-related Pathogenesismentioning

confidence: 99%

“…Among the previously generated transgenic mouse lines expressing CTFs described in Introduction, three lines had been designed to express mutant forms of CTFs, C100(V -I) (Araki et al, 1994), C100(V -F) (Sberna et al, 1998), and C99(I -F) (Rutten et al, 2003), although these transgenic lines do not show any obvious AD-like pathogenesis. In particular, transgenic mice expressing C100(V -F) (Sberna et al, 1998) carry a mutation essentially identical to that of Tg-hCTF99/B6 mice but showed no clear phenotype. Given the severe phenotypes shown by Tg-hCTF99/B6 mice, the absence of a phenotype in their CTFexpressing line may have been due to a low level of transgene expression or a blocking effect due to unidentified genetic backgrounds in a hybrid background.…”

Section: The Roles Of Bctf99 In Ad-related Pathogenesismentioning

confidence: 99%

“…To date, nine research groups have independently created transgenic mouse lines expressing various CTF forms of the human APP in the brain. Five of these lines showed either neuronal atrophy Oster-Granite et al, 1996;Nalbantoglu et al, 1997;Sato et al, 1997) or impaired learning (Nalbantoglu et al, 1997;Berger-Sweeney et al, 1999;Lalonde et al, 2002a) at age 12 -28 months, whereas the other four lines including the recent reported one did not display any obvious neuronal loss or cognitive impairment (Shoji et al, 1990;Sandhu et al, 1991;Araki et al, 1994;Sberna et al, 1998;Li et al, 1999;Rutten et al, 2003). Thus, the developed transgenic mice expressing CTFs showed conflicting results that ranged from no phenotype to AD-like pathogenesis.…”

Section: Introductionmentioning

confidence: 99%

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Progressive neuronal loss and behavioral impairments of transgenic C57BL/6 inbred mice expressing the carboxy terminus of amyloid precursor protein

Lee

Song

et al. 2006

Neurobiology of Disease

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Cholinesterase activity in brain of senescence‐accelerated‐resistant mouse SAMR1 and its variation in brain of senescence‐accelerated‐prone mouse SAMP8

Fernández-Gómez

Muñoz-Delgado

Montenegro

et al. 2009

J of Neuroscience Research

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The early-onset, irreversible, severe deficits of learning and memory in the senescence-accelerated mouse (SAM)-prone/8 (SAMP8) support its use as an animal model for human dementias of early onset. Possible implication of acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) in cognitive dysfunction of SAMP8 mice was studied by comparing cholinesterase (ChE) expression in brains of SAMP8 mice and of their normal control, SAM-resistant/1 (SAMR1) mice. The level of ChE mRNAs was the same in SAMP8 and SAMR1 brains, which agreed with their equal AChE activity (3.09 +/- 1.45 vs. 3.07 +/- 1.44 mumol.hr(-1).mg protein(-1), U/mg), but not with a doubled BuChE activity in SAMP8 brain (0.14 +/- 0.05 vs. 0.07 +/- 0.02 U/mg; P < 0.01). This great increase in neural BuChE activity may contribute to cognitive deficit of SAMP8 mice. Hydrophilic (G(4) (H), 8%) and amphiphilic (G(4) (A), 74%) AChE tetramers, besides dimers and monomers (G(2) (A) + G(1) (A), 18%), were identified in SAMR1 brains. They also contained G(4) (H) BuChE forms (18%) as well as G(4) (A) (53%) and G(2) (A) + G(1) (A) (29%) species. Although SAMP8 brain displayed proportions of AChE and BuChE forms that were similar to those of SAMR1 brain, phenyl-agarose chromatography with detergent-free extracts showed a rise in the proportion of secretory G(4) (H) BuChE from 35% in SAMR1 to 44% in SAMP8 brain. The strong immunolabelling of glial fibrillary acidic protein (GFAP), a marker of reactive gliosis, in SAMP8 brain and the consideration of BuChE as a marker of glial cells suggest a relationship between phenotypic changes in neuroglial cells and the excess of BuChE activity in SAMP8 brain.

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Acetylcholinesterase Is Increased in the Brains of Transgenic Mice Expressing the C‐Terminal Fragment (CT100) of the β‐Amyloid Protein Precursor of Alzheimer's Disease

Abstract: Acetylcholinesterase (AChE)

Cited by 97 publications

References 30 publications

Presenilin 1 Interacts with Acetylcholinesterase and Alters Its Enzymatic Activity and Glycosylation

Presenilin 1 Interacts with Acetylcholinesterase and Alters Its Enzymatic Activity and Glycosylation

Progressive neuronal loss and behavioral impairments of transgenic C57BL/6 inbred mice expressing the carboxy terminus of amyloid precursor protein

Cholinesterase activity in brain of senescence‐accelerated‐resistant mouse SAMR1 and its variation in brain of senescence‐accelerated‐prone mouse SAMP8

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