Changes in acetylcholinesterase expression are associated with altered presenilin-1 levels

Silveyra, María Ximena; García‐Ayllón, María‐Salud; Serra-Basante, Carol; Mazzoni, Valeria; García-Gutierrez, María-Salud; Manzanares, Jorge; Culvenor, Janetta G.; Sáez‐Valero, Javier

doi:10.1016/j.neurobiolaging.2011.04.006

Cited by 25 publications

(31 citation statements)

References 46 publications

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“…It is required for hydrolysis of acetylcholine and it has important roles in zebrafish development as revealed by experiments using ache mutants [19]. ACHE inhibitors are investigated largely as a treatment option for Alzheimer’s disease and an interaction was found between ache and presenilin-1 levels [20]. In our experiments, ache showed a decreased expression during aging (p =?0.0005) and an increased expression in males as compared to females (p =?0.0113) (Figure 3A).…”

Section: Resultsmentioning

confidence: 80%

Gene expression changes in aging Zebrafish (Danio rerio) brains are sexually dimorphic

Arslan-Ergül

Adams

2014

BMC Neurosci

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BackgroundBrain aging is a multi-factorial process due to both genetic and environmental factors. The zebrafish has recently become a popular model organism for examining aging and age-related diseases because as in humans they age gradually and exhibit cognitive decline. Few studies have examined the biological changes in the aging brain that may contribute to these declines and none have examined them within individuals with respect to gender. Our aim was to identify the main genetic pathways associated with zebrafish brain aging across gender. We chose males and females from specific age groups (young, 7.5-8.5 months and old, 31-36 months) based on the progression of cognitive decline in zebrafish. RNA was isolated from individual brains and subjected to microarray and qPCR analysis. Statistical analyses were performed using a two-way ANOVA and the relevant post-hoc tests.ResultsOur results demonstrated that in the brains of young and old male and female zebrafish there were over 500 differentially expressed genes associated with multiple pathways but most notably were those related to neurogenesis and cell differentiation, as well as brain and nervous system development.ConclusionsThe gene expression of multiple pathways is altered with age and differentially expressed in males and females. Future studies will be aimed at determining the causal relationships of age-related changes in gene expression in individual male and female brains, as well as possible interventions that counteract these alterations.

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Section: Resultsmentioning

confidence: 80%

Gene expression changes in aging Zebrafish (Danio rerio) brains are sexually dimorphic

Arslan-Ergül

Adams

2014

BMC Neurosci

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“…However subsequent research suggests that PS1 mRNA levels in human AD brains are significantly higher than in those with no dementia [34,40]. Interestingly, we have shown that Aβ peptide treatment of cultured cells is able to induce increases in cellular PS1 levels [41], probably as part of a vicious cycle of Aβ generation.…”

Section: Discussionmentioning

confidence: 96%

CSF Presenilin-1 complexes are increased in Alzheimer’s disease

García‐Ayllón

Campanari

Brinkmalm

et al. 2013

acta neuropathol commun

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BackgroundPresenilin-1 (PS1) is the active component of the amyloid precursor protein cleaving γ-secretase complex. PS1 protein is a transmembrane protein containing multiple hydrophobic regions which presence in cerebrospinal fluid (CSF) has not been measured to date. This study assesses whether PS1 and other components of the γ-secretase complex are present in CSF.ResultsHere, we show that PS1 is present in ventricular post-mortem and lumbar ante-mortem CSF, and plasma as 100–150-kDa hetero-complexes containing both the N- and C-terminal fragments (NTF and CTF) of the protein. Immunoprecipitation and immunoblotting with different antibodies confirmed the identity of the PS1 species. The γ-secretase components, APH-1 (anterior pharynx-defective 1) and PEN-2 (presenilin enhancer 2), as well as presenilin-2 (PS2) fragments, co-exist within these CSF complexes, while nicastrin is not detected. These CSF-PS1 complexes differ from active γ-secretase membrane-complexes, and may represent nonspecific aggregation of the PS1 protein. Levels of PS1 complexes are increased in CSF samples from autopsy-confirmed Alzheimer’s disease (AD) cases and were found to be more stable than complexes in CSF from control subjects. Despite similar levels of total PS1 in CSF from probable AD patients and cognitively normal subjects, an increased proportion of highly stable PS1 complexes were observed in AD CSF.ConclusionsOur data suggest that fragments of the PS1 protein present in CSF as complexes may be useful as a biomarker for AD.

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“…Thus, PS are a potential drug target not only for neurodegenerative diseases with a genetic PS involvement, but also for age-related motor deficits. Of therapeutic relevance, targeting PS may overcome the poor outcomes associated with targeting the cholinergic system, which have yielded only short-term effects on PS1 [45]. …”

Section: Resultsmentioning

confidence: 99%

“…However, this study did not address any regional expression differences or functional/behavioral consequences of the change in PS expression, and there is no published report on the expression of PS protein in senescent mice older than 15 mo. Furthermore, PS expression is directly associated with the expression levels of acetylcholinesterase [45]. Given the well-documented age-related changes of the cholinergic system [46], differential changes in PS expression levels during aging are likely to occur.…”

Section: Discussionmentioning

confidence: 99%

“…Other physiological functions of presenilins, most notably their role as a core component of the γ-secretase complex, may, however, contribute in parallel to the involvement of PS in normal brain aging and age-related disorders of the CNS. Notably, PS expression is affected by sex, steroid hormones, and cellular levels of oxidative stress, which are increased during neurodegenerative diseases and aging [57,58,44,59,45]. Little is known, however, regarding the expression during aging or correlation with performance in behavioral paradigms of the other subunits of the γ-secretase complex.…”

Section: Discussionmentioning

confidence: 99%

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Loss of Spatial Memory, Learning, and Motor Function During Normal Aging Is Accompanied by Changes in Brain Presenilin 1 and 2 Expression Levels

Kaja

Sumien²,

Shah

et al. 2014

Mol Neurobiol

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Mutations in presenilin (PS) proteins cause familial Alzheimer’s disease. We herein tested the hypothesis that the expression levels of PS proteins are differentially affected during healthy aging, in the absence of pathological mutations. We used a preclinical model for aging to identify associations between PS expression and quantitative behavioral parameters for spatial memory and learning and motor coordination. We identified significant changes of PS protein expression in both cerebellum and forebrain that correlated with the performance in behavioral paradigms for motor coordination and memory and learning. Overall, PS1 levels were decreased, while PS2 levels were increased in aged mice compared with young controls. Our study presents novel evidence for the differential expression of PS proteins in a non-genetic model for aging, resulting in an overall increase of the PS2 to PS1 ratio. Our findings provide a novel mechanistic basis for molecular and functional changes during normal aging.

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Changes in acetylcholinesterase expression are associated with altered presenilin-1 levels

Cited by 25 publications

References 46 publications

Gene expression changes in aging Zebrafish (Danio rerio) brains are sexually dimorphic

Gene expression changes in aging Zebrafish (Danio rerio) brains are sexually dimorphic

CSF Presenilin-1 complexes are increased in Alzheimer’s disease

Loss of Spatial Memory, Learning, and Motor Function During Normal Aging Is Accompanied by Changes in Brain Presenilin 1 and 2 Expression Levels

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