Genetic deletion of α7 nicotinic acetylcholine receptors induces an age-dependent Alzheimer's disease-like pathology

The accumulation of amyloid-beta peptide (A beta) and the failure of cholinergic transmission are key players in Alzheimer's disease (AD). However, in the healthy brain, A beta contributes to synaptic plasticity and memory acting through alpha 7 subtype nicotinic acetylcholine receptors (alpha 7nAChRs). Here, we hypothesized that the alpha 7nAChR deletion blocks A beta physiological function and promotes a compensatory increase in A beta levels that, in turn, triggers an AD-like pathology. To validate this hypothesis, we studied the age-dependent phenotype of alpha 7 knock out mice. We found that alpha 7nAChR deletion caused an impairment of hippocampal synaptic plasticity and memory at 12 months of age, paralleled by an increase of Amyloid Precursor Protein expression and A beta levels. This was accompanied by other classical AD features such as a hyperphosphorylation of tau at residues Ser 199, Ser 396, Thr 205, a decrease of GSK-3 beta at Ser 9, the presence of paired helical filaments and neurofibrillary tangles, neuronal loss and an increase of GFAP-positive astrocytes. Our findings suggest that alpha 7nAChR malfunction might precede A beta and tau pathology, offering a different perspective to interpret the failure of anti-A beta therapies against AD and to find novel therapeutical approaches aimed at restoring alpha 7nAChRs-mediated A beta function at the synapse.

Automated summary

The deletion of alpha 7nAChR leads to impaired hippocampal synaptic plasticity and memory, along with an increase in Amyloid Precursor Protein expression and A beta levels, resembling classic features of Alzheimer's disease (AD).