Beyond the cholinergic hypothesis: do current drugs work in Alzheimer's disease?

Abstract

Alzheimer's disease (AD) is a neurodegenerative disease characterized by memory and cognitive loss, and represents the leading cause of dementia in elderly people. Besides the complex biochemical processes involved in the neuronal degeneration (formation of senile plaques containing Abeta peptides, and development of neurofibrillary tangles), other molecular and neurochemical alterations, like cholinergic deficit due to basal forebrain degeneration, also occur. Because acetylcholine has been demonstrated to be involved in cognitive processes, the idea to increase acetylcholine levels to restore cognitive deficits has gained interest (the so-called cholinergic hypothesis). This has led to the development of drugs able to prevent acetylcholine hydrolysis (acetylcholinesterase inhibitors). However, the analysis of clinical efficacy of these drugs in alleviating symptoms of dementia showed unsatisfactory results. Despite such critical opinions on the efficacy of these drugs, it should be said that acetylcholinesterase inhibitors, and for some aspects memantine also, improve memory and other cognitive functions throughout most of the duration of the disease. The pharmacological activity of these drugs suggests an effect beyond the mere increase of acetylcholine levels. These considerations are in agreement with the idea that cognitive decline is the result of a complex and not fully elucidated interplay among different neurotransmitters. The role of each of the neurotransmitters implicated has to be related to a cognitive process and as a consequence to its decline. The current review aims to highlight the positive role of cholinergic drugs in alleviating cognitive deficits during wake as well as sleep. Moreover, we suggest that future therapeutic approaches have to be developed to restore the complex interplay between acetylcholine and other neurotransmitters systems, such as dopamine, serotonin, noradrenaline, or glutamate, that are likely involved in the progressive deterioration of several cognitive functions such as attention, memory, and learning.

Figure 1

Summary of the synthetic pathway of acetylcholine. Principle of AcheIs functioning. Presynaptic cholinergic neuron synthesise acetylcholine (ACh) from choline and acetyl‐CoA. Choline‐acetyl transferase (ChAT) is the limiting rate enzyme for synthesis of Ach. It is stored in vescicles, and then released in the synaptic cleft. ACh acts on postsynaptic neurons on M1 subtype of muscarinic receptors and also on nicotinic receptors; in particular, the α7 nicotinic receptor is involved in most of the ACh effects on cognitive functions. ACh is then hydrolized through the enzyme acetylcholine‐esterase (AChE), allowing for its reuptake through the choline transporter and the high‐affinity choline transporter (HACU). To replace cholinergic transmission in patients with a diagnosis of AD, drugs able to inhibit AChE (AChEI) were developed, to increase the level and action duration of the neurotransmitter ACh. (“cholinergic hypothesis”).

Figure 2

Ach inhibits sleep‐promoting neurones in the SCN. Hypothalamic supra‐chiasmatic nucleus (SCN) neurons are considered sleep‐promoting neurons. SCN neurones send projections to the histaminergic (H) tubero‐mammilary nucleus (TMN), a hypothalamic nucleus involved in arousal and cortical activation. Moreover, SCN neurones are also reciprocally connected with the activating systems, namely locus coeruleus (LC) and the cholinergic pontine tegmental system (PPT). NA as well as ACh are able to inhibit SCN neurons, maintaining wakefulness. NA, released from LC terminals, exert an inhibitory effect through the activation of postsynaptic α2‐adrenergic receptors. At the same time, LC projects to the PPT, exerting an excitatory effect on cholinergic neurons acting on postsynaptic α1‐adrenergic receptors set on these neurons. This effect is made possible also due to the inhibition of GABA neurons of the tegmental region: inhibition mediated through α2‐adrenergic receptors. PPT releases Ach, which acts inhibiting SCN neurons directly via the postsynaptic muscarinic receptors and indirectly modulating the nicotinic receptors, localized on presynaptic terminals from LC. The effect of ACh is present during waking, although aminergic tone is prevalent, and during REM sleep, where it plays a fundamental role in memory consolidation. In the control of circadian rhythm are involved other transmitters playing function not fully known. Among others, orexin and adenosine are involved in the control of wake–sleep cycle, with opposite effect. Orexin, released from hypothalamic neurones acts trough two different types of receptor differently expressed in LC (OX1), or TMN (OX2), where OX1 seem to be related more with vigilance. Adenosine (Ado) coreleased with neurotransmitters, exerts excitatory effects on PPT neurones modulating ACh release, and also on SCN neurones having a modulatory role during sleep induction.

Figure 3

“Neuroprotective effects of ChEIS. Role of α7 nicotinic receptor.” Under normal conditions ChEIS (in particular, Donepezil or Galantamine) stimulate nAChr, likely through an allosteric site distinct from the acrtylcholinesterase binding site (which is known for galantamine while only suggested for donepezil). Upon stimulation of these drugs α7 nAChR activates phospatidylinositol 3‐kinase (PI3K), through the activation and association of Janus‐activated kinase 2 (JAK2) and with nonreceptor type tyrosine kinase Fyn. PI3K activated in turn leads to the activation of Akt by phosphorylation (Akt‐p). The level of Akt‐p increases upon nicotine treatment. Its activation increases the expression level of Bcl‐2 transcript, protecting neurons from cell death. Hypoactivated α7 nAChR decreases the activation of Jak2 and PI3K, which in turn increases the activity of the GSK‐3β enzyme, leading to increased phosphorilation of tau proteins, until cell death.