Alpha7 nicotinic acetylcholine receptor: a link between inflammation and neurodegeneration

Abstract

Alzheimer's disease (AD) is the leading cause of dementia affecting over 25 million people worldwide. Classical studies focused on the description and characterization of the pathological hallmarks found in AD patients including the neurofibrillary tangles and the amyloid plaques. Current strategies focus on the etiology of these hallmarks and the different mechanisms contributing to neurodegeneration. Among them, recent studies reveal the close interplay between the immunological and the neurodegenerative processes. This article examines the implications of the alpha7 nicotinic acetylcholine receptor (alpha7nAChR) as a critical link between inflammation and neurodegeneration in AD. Alpha7nAChRs are not only expressed in neurons but also in Glia cells where they can modulate the immunological responses contributing to AD. Successful therapeutic strategies against AD should consider the connections between inflammation and neurodegeneration. Among them, alpha7nAChR may represent a pharmacological target to control these two mechanisms during the pathogenesis of neurodegenerative and behavioral disorders.

Fig. 1

Characteristic pathological mechanisms and hallmarks found in AD patients. The typical pathological hallmarks of AD include the neurofibrillary tangles and amyloid plaques that represent the two characteristic biochemical processes of the disease: hyperphosphorylation of tau and misfolding of amyloid beta. Hyperphosphorylation of tau in AD patients favors its dissociation from the microtubules and its accumulation in paired helical filaments (PHFs). PHFs aggregate into detrimental clusters inside nerve cell bodies known as neurofibrillary tangles and as dystrophic neurites associated with amyloid plaques. The massive dissociation of tau from microtubules also interferes with the axonal transport and contributes to the loss of synapses and neuronal degeneration correlated with the cognitive impairments of the AD patients. AD is also associated with the accumulation of abnormal folded amyloid beta_1–42 (Aβ42) in the amyloid plaques. More comprehensive strategies are currently directed to determine the etiology of AD and the potential contribution of inflammation to both the pathogenesis and prognosis of AD.

Fig. 2

Effect of nicotine-alpha7nAChRs interaction on tau phosphorylation. The nicotine-alpha7nAChRs interaction inhibits the production of TNF in LPS-stimulated mouse microglial cultures through inhibition of the NF-κB pathway. This inhibition of TNF is associated with a reduction in phosphorylation of ERK and p38 MAPK. P38 MAPK can phosphorylates tau in neurons and glia. A reduction of p38 MAPK may prevent tau phosphorylation at S202, S296, S422 and T181. Activated microglia colocalize with amyloid plaques and facilitate amyloid clearance but can also phosphorylate tau through release of proinflammatory cytokines (including TNF), chemokines and other inflammatory components. Activation of the cdk5/p25 complex has also been proposed as underlying mechanism in the phosphorylation of tau at S202 and S235.

Fig. 3

Schematic diagram showing the phospho tau epitopes affected by the Abeta42-alpha7nAChR interaction and the kinases activated by TNF in the longest isoform of tau. Tau isoforms are generated by splicing in or out exons 2, 3 and 10 (E2, E3 and E10). Red rhomboids are the different antibodies at specific phospho-tau epitopes. Abeta42 can phosphorylate tau at specific sites (T181, S202, T231 and S396/404) and TNF can activate kinases cdk5 and p38MAPK that phosphorylate tau at S202 and S235 (cdk5) and T181, S202, S396 and S422 (p30MAPK).

Fig. 4

Schematic of the nicotinic-alpha7nAChR mediated activation of Jak2 neuroprotective pathway. The Abeta42-alpha7nAChR interaction activates the apoptotic enzyme caspase 3 and produces cleavage of the DNA-repairing enzyme poly-(ADP-ribose) polymerase causing eventually neurotoxicity and cell death. This cascade is inhibited by nicotinic activation of the JAK2-PI3K-Akt signaling pathway, promoting neuroprotection and cell survival. Activation of the anti-apoptotic kinase Akt involves phosphorylation of the forkhead transcription factor (FKHRL1), blocking eventually the expression of the apoptotic FAS protein. The Abeta42-alpha7nAChR interaction also produces increases in intracellular Ca²⁺ with activation of mitogen-activated kinase proteins ERK and JNK inducing tau hyperphosphorylation.