Transgenic expression of human acetylcholinesterase induces progressive cognitive deterioration in mice

Beeri, Rachel; Andres, Christian R.; Lev-Lehman, Efrat; Timberg, Rina; Huberman, T.; Shani, Moshe; Soreq, Hermona

doi:10.1016/s0960-9822(95)00211-9

Cited by 128 publications

(72 citation statements)

References 45 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…11 In the social recognition paradigm, they failed to remember a conspecific juvenile, even following a delay interval of only 5 min. This extends previous reports on their spatial learning and memory impairments 9,10 and agrees with previous reports 22,27 on the social behavior changes associated with cholinergic impairments.…”

Section: Discussionsupporting

confidence: 93%

“…9 Control, nonTg FVB/N mice were obtained by littermate breeding. Adult, [8][9][10][11][12][13][14][15][16][17][18][19][20] wk old Tg and control male mice were housed 4-5 per cage in a 12 h dark/light cycle with free access to food and water. All experiments were conducted during the first half of the dark phase of a reversed 12 h dark/light cycle, under dim illumination.…”

Section: Animalsmentioning

confidence: 99%

See 1 more Smart Citation

Neuronal overexpression of ‘readthrough’ acetylcholinesterase is associated with antisense-suppressible behavioral impairments

et al. 2002

View full text Add to dashboard Cite

Molecular origin(s) of the diverse behavioral responses to anticholinesterases were explored in behaviorally impaired transgenic (Tg) FVB/N mice expressing synaptic human acetylcholinesterase (hAChE-S). Untreated hAChE-S Tg, unlike naïve FVB/N mice, presented variably intense neuronal overexpression of the alternatively spliced, stress-induced mouse 'readthrough' mAChE-R mRNA. Both strains displayed similar diurnal patterns of locomotor activity that were impaired 3 days after a day-to-night switch. However, hAChE-S Tg, but not FVB/N mice responded to the circadian switch with irregular, diverse bursts of increased locomotor activity. In social recognition tests, controls displayed short-term recognition, reflected by decreased exploration of a familiar, compared to a novel juvenile conspecific as well as inverse correlation between social recognition and cortical and hippocampal AChE specific activities. In contrast, transgenics presented poor recognition, retrievable by tetrahydroaminoacridine (tacrine, 1.5 mg kg −1 ). Tacrine's effect was short-lived (Ͻ40 min), suggesting its effect was overcome by anticholinesterase-induced overproduction of mAChE-R. Consistent with this hypothesis, antisense oligonucleotides (two daily intracerebroventricular injections of 25 ng) arrested mAChE-R synthesis, selectively reduced mAChE-R levels and afforded an extended (Ͼ24 h) suppression of the abnormal social recognition pattern in transgenics. Efficacy of antisense treatment was directly correlated with AChE-R levels and the severity of the impaired phenotype, being most apparent in transgenics presenting highly abnormal pretreatment behavior. These findings demonstrate that neuronal AChE-R overproduction is involved in various behavioral impairments and anticholinesterase responses, and point to the antisense strategy as a potential approach for re-establishing cholinergic balance.

show abstract

Section: Discussionsupporting

confidence: 93%

Section: Animalsmentioning

confidence: 99%

Neuronal overexpression of ‘readthrough’ acetylcholinesterase is associated with antisense-suppressible behavioral impairments

et al. 2002

View full text Add to dashboard Cite

show abstract

“…Compelling evidence suggests an important role of the cholinergic system in the control of locomotor activity (Beeri et al., 1995; Martins‐Silva et al., 2011; Miyakawa, Yamada, Duttaroy, & Wess, 2001; Shapovalova, Kamkina, & Mysovskii, 2005). However, the role of M 4 receptors in the control of locomotor activity remains elusive.…”

Section: Discussionmentioning

confidence: 99%

The deletion of M₄ muscarinic receptors increases motor activity in females in the dark phase

et al. 2018

View full text Add to dashboard Cite

ObjectivesM4 muscarinic receptors (MR) presumably play a role in motor coordination. Previous studies have shown different results depending on genetic background and number of backcrosses. However, no attention has been given to biorhythms.Material and MethodsWe therefore analyzed biorhythms under a light/dark cycle obtained telemetrically in intact animals (activity, body temperature) in M4 KO mice growth on the C57Bl6 background using ChronosFit software. Studying pure effects of gene knockout in daily rhythms is especially important knowledge for pharmacological/behavioral studies in which drugs are usually tested in the morning.ResultsWe show that M4 KO mice motor activity does not differ substantially from wild‐type mice during light period while in the dark phase (mice active part of the day), the M4 KO mice reveal biorhythm changes in many parameters. Moreover, these differences are sex‐dependent and are evident in females only. Mesor, night–day difference, and night value were doubled or tripled when comparing female KO versus male KO. Our in vitro autoradiography demonstrates that M4 MR proportion represents 24% in the motor cortex (MOCx), 30% in the somatosensory cortex, 50% in the striatum, 69% in the thalamus, and 48% in the intergeniculate leaflet (IGL). The M4 MR densities were negligible in the subparaventricular zone, the posterior hypothalamic area, and in the suprachiasmatic nuclei.ConclusionsWe conclude that cholinergic signaling at M4 MR in brain structures such as striatum, MOCx, and probably with the important participation of IGL significantly control motor activity biorhythm. Animal activity differs in the light and dark phases, which should be taken into consideration when interpreting the results.

show abstract

“…AChE proteins are intimately associated with the AD senile plaques and neurofibrillary tangles (Ulrich et al, 1990;Moran et al, 1993) and facilitate the growth of fibrillar ␤-amyloid plaques (Inestrosa et al, 1996). In addition, transgenic mice overexpressing AChE exhibit loss of dendritic spines and suffer from cognitive deficits (Beeri et al, 1995). Furthermore, when crossed with ␤-APP (␤-amyloid precursor protein) transgenics, the AChE transgenics develop amyloid plaques earlier than the parent strain (Rees et al, 2003).…”

Section: Discussionmentioning

confidence: 99%

Excessive Expression of Acetylcholinesterase Impairs Glutamatergic Synaptogenesis in Hippocampal Neurons

Dong¹,

Yun²,

Farchi³

et al. 2004

J. Neurosci.

View full text Add to dashboard Cite

Acetylcholinesterase (AChE) exerts noncatalytic activities on neural cell differentiation, adhesion, and neuritogenesis independently of its catalytic function. The noncatalytic functions of AChE have been attributed to its peripheral anionic site (PAS)-mediated proteinprotein interactions. Structurally, AChE is highly homologous to the extracellular domain of neuroligin, a postsynaptic transmembrane molecule that interacts with presynaptic ␤-neurexins, thus facilitating synaptic formation and maturation. Potential effects of AChE expression on synaptic transmission, however, remain unknown. Using electrophysiology, immunocytochemistry, and molecular biological approaches, this study investigated the role of AChE in the regulation of synaptic formation and functions. We found that AChE was highly expressed in cultured embryonic hippocampal neurons at early culture days, particularly in dendritic compartments including the growth cone. Subsequently, the expression level of AChE declined, whereas synaptic activity and synaptic proteins progressively increased. Chronic blockade of the PAS of AChE with specific inhibitors selectively impaired glutamatergic functions and excitatory synaptic structures independently of cholinergic activation, while inducing AChE overexpression. Moreover, the PAS blockade-induced glutamatergic impairments were associated with a depressed expression of ␤-neurexins and an accumulation of other synaptic proteins, including neuroligins, and were mostly preventable by antisense suppression of AChE expression. Our findings demonstrate that interference with the nonenzymatic features of AChE alters AChE expression, which impairs excitatory synaptic structure and functions.

show abstract

Transgenic expression of human acetylcholinesterase induces progressive cognitive deterioration in mice

Abstract: We conclude that upsetting cholinergic balance may by itself cause progressive memory decline in mammals, suggesting that congenital and/or acquired changes in this vulnerable balance may contribute to the physiopathology of Alzheimer's disease.

Cited by 128 publications

References 45 publications

Neuronal overexpression of ‘readthrough’ acetylcholinesterase is associated with antisense-suppressible behavioral impairments

Neuronal overexpression of ‘readthrough’ acetylcholinesterase is associated with antisense-suppressible behavioral impairments

The deletion of M₄ muscarinic receptors increases motor activity in females in the dark phase

Excessive Expression of Acetylcholinesterase Impairs Glutamatergic Synaptogenesis in Hippocampal Neurons

Contact Info

Product

Resources

About

Transgenic expression of human acetylcholinesterase induces progressive cognitive deterioration in mice

Abstract: We conclude that upsetting cholinergic balance may by itself cause progressive memory decline in mammals, suggesting that congenital and/or acquired changes in this vulnerable balance may contribute to the physiopathology of Alzheimer's disease.

Cited by 128 publications

References 45 publications

Neuronal overexpression of ‘readthrough’ acetylcholinesterase is associated with antisense-suppressible behavioral impairments

Neuronal overexpression of ‘readthrough’ acetylcholinesterase is associated with antisense-suppressible behavioral impairments

The deletion of M4 muscarinic receptors increases motor activity in females in the dark phase

Excessive Expression of Acetylcholinesterase Impairs Glutamatergic Synaptogenesis in Hippocampal Neurons

Contact Info

Product

Resources

About

The deletion of M₄ muscarinic receptors increases motor activity in females in the dark phase