Competitive substrate inhibition in the histochemistry of cholinesterase activity in Alzheimer's disease

Schätz, Christoph R.; Geula, Changiz; Mesulam, M. Marsel

doi:10.1016/0304-3940(90)90119-t

Cited by 25 publications

(10 citation statements)

References 10 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…This association of AChE with b-amyloid induces alterations in some of the enzyme properties (pH sensitivity, substrate concentration) and increases the neurotoxicity of Alzheimer fibrils (15,16), which correlates with corresponding findings in senile plaques from Alzheimer brains (17,18). A role of AChE in b-amyloid plaque formation was also supported by in vivo studies.…”

Section: Cholinergic Neurotransmission B-amyloid and App Processing supporting

confidence: 59%

Basal Forebrain Cholinergic Dysfunction in Alzheimer’s Disease – Interrelationship with β-amyloid, Inflammation and Neurotrophin Signaling

Schliebs

2005

Neurochem Res

154

View full text Add to dashboard Cite

Alzheimer's disease, the most common neurodegenerative disorder of senile dementia, is characterized by two major morpho-pathological hallmarks. Deposition of extracellular neuritic, beta-amyloid peptide-containing plaques (senile plaques) in cerebral cortical regions of Alzheimer patients is accompanied by the presence of intracellular neurofibrillary tangles in cerebral pyramidal neurons. Basal forebrain cholinergic dysfunction is also a consistent feature of Alzheimer's disease, which has been suggested to cause, at least partly, the cognitive deficits observed in patients with Alzheimer's disease. Impaired cortical cholinergic neurotransmission may also contribute to beta-amyloid plaque pathology in Alzheimer's disease by affecting expression and processing of the beta-amyloid precursor protein (APP). Vice versa, low level of soluble beta-amyloid has been observed to inhibit cholinergic synaptic function. Deposition of beta-amyloid plaques in Alzheimer's disease is also accompanied by a significant plaque-associated glial up-regulation of interleukin-1, which has been attributed to affect expression and metabolism of APP and to interfere with cholinergic transmission. Understanding the molecular mechanisms underlying the interrelationship between cortical cholinergic dysfunction, beta-amyloid formation and deposition, as well as local inflammatory upregulation, would allow to derive potential treatment strategies to pharmacologically intervene in the disease-causing signaling cascade.

show abstract

Section: Cholinergic Neurotransmission B-amyloid and App Processing supporting

confidence: 59%

Basal Forebrain Cholinergic Dysfunction in Alzheimer’s Disease – Interrelationship with β-amyloid, Inflammation and Neurotrophin Signaling

Schliebs

2005

Neurochem Res

154

View full text Add to dashboard Cite

show abstract

“…A selective loss of the G4 form occurs in post-mortem brain from Alzheimer's patients (15). Additionally, changes in enzyme distribution and substrate properties have been reported (71,174,175,227). In brains from Alzheimer patients, there is a shift in both AChE and BuChE activities away from the neuronal pathways to the neuritic plaques and neurofibrillary tangles.…”

Section: Changes In Cholinesterases During Diseasementioning

confidence: 99%

The Pharmacology of Physostigmine

Triggle

Mitchell

Filler³

1998

CNS Drug Reviews

140

View full text Add to dashboard Cite

“…Most of the cortical AChE activity present in Alzheimer's brain is predominantly associated with the amyloid core of senile plaques rather than with the neuritic component found at the periphery (Ulrich et al, 1990;Gómez-Ramos et al, 1992;Morán et al, 1993). Histochemical studies have demonstrated that the AChE associated with senile plaques differs enzymatically from the AChE associated with normal fibers and neurons with respect to optimum pH, inhibitor sensitivity, and inhibition by excess substrate (Mesulam et al, 1987;Geula and Mesulam, 1989;Schätz et al, 1990;Wright et al, 1993). AChE directly promotes the assembly of A␤ peptide into amyloid fibrils (Alvarez et al, 1995;Inestrosa et al, 1996b), and recent studies from our laboratory have shown that AChE forms complexes with small A␤ peptide fragments .…”

mentioning

confidence: 99%

Stable Complexes Involving Acetylcholinesterase and Amyloid-β Peptide Change the Biochemical Properties of the Enzyme and Increase the Neurotoxicity of Alzheimer’s Fibrils

et al. 1998

View full text Add to dashboard Cite

Brain acetylcholinesterase (AChE) forms stable complexes with amyloid-␤ peptide (A␤) during its assembly into filaments, in agreement with its colocalization with the A␤ deposits of Alzheimer's brain. The association of the enzyme with nascent A␤ aggregates occurs as early as after 30 min of incubation. Analysis of the catalytic activity of the AChE incorporated into these complexes shows an anomalous behavior reminiscent of the AChE associated with senile plaques, which includes a resistance to low pH, high substrate concentrations, and lower sensitivity to AChE inhibitors. Furthermore, the toxicity of the AChE-amyloid complexes is higher than that of the A␤ aggregates alone. Thus, in addition to its possible role as a heterogeneous nucleator during amyloid formation, AChE, by forming such stable complexes, may increase the neurotoxicity of A␤ fibrils and thus may determine the selective neuronal loss observed in Alzheimer's brain.

show abstract

Competitive substrate inhibition in the histochemistry of cholinesterase activity in Alzheimer's disease

Cited by 25 publications

References 10 publications

Basal Forebrain Cholinergic Dysfunction in Alzheimer’s Disease – Interrelationship with β-amyloid, Inflammation and Neurotrophin Signaling

Basal Forebrain Cholinergic Dysfunction in Alzheimer’s Disease – Interrelationship with β-amyloid, Inflammation and Neurotrophin Signaling

The Pharmacology of Physostigmine

Stable Complexes Involving Acetylcholinesterase and Amyloid-β Peptide Change the Biochemical Properties of the Enzyme and Increase the Neurotoxicity of Alzheimer’s Fibrils

Contact Info

Product

Resources

About