The review examines the multifaceted interactions between cholinergic transmission
and beta-amyloid suggesting a continuum in the action of the peptide that at low concentrations
(picomolar-low nanomolar) may directly stimulate nicotinic cholinergic receptor while
desensitizing them at increasing concentrations (high nanomolar-low micromolar). In
addition high beta-amyloid concentrations may reduce the synaptic release of several
neurotransmitters, including glutamate, aspartate, GABA, glycine and dopamine, when
the release is elicited through cholinergic stimulation but not following depolarization.
The effect of beta-amyloid has been observed both in vitro and in vivo in at least
three different brain areas (nucleus accumbens, striatum, hippocampus) suggesting
that the peptide may exert some general effects even if not all the brain areas have
been evaluated. In turn the activation of cholinergic receptors may affect the amyloid
precursor protein processing diverting the metabolism toward non-amyloidogenic products.
These actions, dissociated from those described in the case of high beta-amyloid concentrations
leading to neurotoxic oligomers, may participate to cause dysfunctions in the neurotransmitter
activity, in turn leading, at least from a theoretical point of view, to early neuropsychiatric
disturbances in the disease. Complexively these observations underscore novel relationships
between two main players in Alzheimer's disease pathogenesis that are beta-amyloid
and cholinergic transmission. Also emerges the inherent difficulty of targeting beta-amyloid
in a context in which the peptide exerts several actions beyond neurotoxicity.