The Cholinergic System, the Adrenergic System and the Neuropathology of Alzheimer's Disease

Abstract

Neurodegenerative diseases are a major public health problem worldwide with a wide spectrum of symptoms and physiological effects. It has been long reported that the dysregulation of the cholinergic system and the adrenergic system are linked to the etiology of Alzheimer's disease. Cholinergic neurons are widely distributed in brain regions that play a role in cognitive functions and normal cholinergic signaling related to learning and memory is dependent on acetylcholine. The Locus Coeruleus norepinephrine (LC-NE) is the main noradrenergic nucleus that projects and supplies norepinephrine to different brain regions. Norepinephrine has been shown to be neuroprotective against neurodegeneration and plays a role in behavior and cognition. Cholinergic and adrenergic signaling are dysregulated in Alzheimer's disease. The degeneration of cholinergic neurons in nucleus basalis of Meynert in the basal forebrain and the degeneration of LC-NE neurons were reported in Alzheimer's disease. The aim of this review is to describe current literature on the role of the cholinergic system and the adrenergic system (LC-NE) in the pathology of Alzheimer's disease and potential therapeutic implications.

Keywords: Alzheimer; Locus Coeruleus; acetylcholine; adrenergic; cholinergic; cognition; epigenetics; norepinephrine; signaling.

Figure 1

The role of acetylcholine at synapses. Choline is the main precursor for the formation of acetylcholine (Ach). Via the activity of choline acetyltransferase (ChAT), Ach is formed from choline and Acetyl-CoA. Once released at synapses, Ach binds to nicotinic or muscarinic receptors on postsynaptic neurons to regulate cholinergic signaling in different brain regions. Excess Ach at synapses is converted to choline and acetate via the activity of acetylcholine esterase (AchE). Choline is then recycled back to the presynaptic neuron via the presence of specific choline transporters such as CHT1.

Figure 2

The role of norepinephrine at synapses. Norepinephrine is synthesized in a multistep process. Tyrosine is converted to L-DOPA via the activity of tyrosine hydroxylase (TH). L-DOPA is then decarboxylated via DOPA decarboxylase into dopamine. Dopamine via dopamine beta-hydroxylase (DBH) is then converted to norepinephrine (NE). NE is released at synapses where it can bind to α- adrenergic receptors or β- adrenergic receptors on postsynaptic neurons to modulate neuronal firing or modulate adrenergic neurons signaling. NE excess can be eliminated via the activity of monoamine oxidase (MAO) or catechol-O-methyltransferase (COMT). NE can also be recycled back to presynaptic neurons via the NE transporters (NET).

Figure 3

The role of epigenetic mechanisms in modulation of gene expression. This figure provides an overview of the role of epigenetic mechanisms in modulation of the genome and the consequences of such modulation on phenotype. These mechanisms include DNA methylation of genes, changes in specific histone marks along genes or changes in the expression of genes by specific microRNAs.