Classical Alzheimer features and cholinergic dysfunction: towards a unifying hypothesis?

Abstract

Objective – Our autopsy studies show possible links between classical Alzheimer pathology and decreased expression of nicotinic acetylcholine receptors. For further elucidation we are now using in vitro models. We report preliminary evidence for the impact of β‐amyloid on nicotinic receptor expression in hippocampal dissociation culture. Methods – Cultures (E18 rats) were grown in a serum‐free medium and incubated at 8 days in vitro for 3 days with 1 µM Aβ1–42. Expression of α4, α7, and β2 nicotinic receptor subunit protein was assessed immunohistochemically and rated semiquantitatively. Results – Aβ1–42 incubation resulted in a massive reduction of α4 protein‐expressing neurons, this effect was less pronounced for the α7 and β2 subunit protein. Conclusion – These findings provide first evidence for a direct impact of classical Alzheimer pathology features on nicotinic receptor expression in vitro. Our model will be useful for testing the potential of drugs to stop or reverse these effects.

Role of Oxidative Stress in the Progression of Alzheimer's Disease

“…AD is associated with cholinergic neuronal loss [115][116][117][118][119]. The loss of cholinergic neurons is consistent with the reported decreased levels of acetylcholine, an important neurotransmitter, in AD brain.…”

“…PEBP may also play an important role in maintaining phospholipid asymmetry. That neuropolypeptide h3 is found to be oxidatively modified protein in both AD and MCI brain [38,73] suggests altered activity of this enzyme to carry out its function and could contribute to the consequent decreased acetylcholine levels in AD brain [115][116][117]120,121]. Further, the level of PEBP is reported to be decreased in AD brain.…”

β-Amyloid Peptide Activates Non-α7 Nicotinic Acetylcholine Receptors in Rat Basal Forebrain Neurons

“…Although the mechanisms leading to the degeneration of cholinergic neurons are still unclear, there is evidence to link the loss of the basal forebrain cholinergic neurons to memory and cognitive deficits observed in AD patients (Price 1986). Postmortem analysis of brain tissue from the temporal cortex of AD patients shows a selective loss of the ␣4, but not ␣7 or ␣3, nAChR subunits (Martin-Ruiz et al 1999;Warpman and Nordberg 1995;Wevers et al 2000). Studies that have examined a potential neuroprotective role for nicotinic receptor modulators have yielded conflicting results.…”

Roles of amyloid β-peptide-associated oxidative stress and brain protein modifications in the pathogenesis of Alzheimer's disease and mild cognitive impairment

“…N-methyl-D-aspartic acid (NMDA) receptors activate the production of this enzyme, and alteration of the NMDA receptor mediates cholinergic deficits [213]. Alzheimer's disease is associated with cholinergic neuronal loss [214][215][216]. Since neuropolypeptide h3 is also PEBP, it is possible that lipid asymmetry is also affected by oxidized PEBP.…”