Abstract Body

Objectives:
Activation of the M1 muscarinic acetylcholine receptor (M1mAChR) is a validated target for the treatment of cognitive dysfunction in schizophrenia and Alzheimer's disease (AD) as this receptor has a pivotal role in modulating cognitive deficits and the pathology of the disease. NSC001, a highly rigid M1 selective and specific orthosteric partial agonist, fulfills stringent acceptance criteria for a CNS-favored drug including but not limited to CNS-selectivity, target specificity, and oral bioavailability.


Methods, Results:
In neurons, NSC001 via binding to M1 mAChR –i) activates ADAM17 and inhibits BACE1 leading to a decrease of Abeta and C99 and an increase of alphaAPPs and C88; ii) inhibits GSK-3beta leading to decreased Abeta-induced apoptosis and tau-p; and iii) potentiates the cleavage of cellular prion protein (PrP^c) to the C1 and the neuroprotective N1 fragment through PKC-dependent phosphorylation of ADAM17. This may prevent binding of Abeta oligomers to PrP^c, long-term potentiation inhibition, and cognitive deficits. In microglia, NSC001 activates alpha-secretase leading to soluble triggering receptor expressed on myeloid cells 2 (sTREM2) elevation without changing total TREM2. Therefore, NSC001 may overcome microglial dysfunction in neurodegeneration. In several animal models, NSC001 targeted beneficially major hallmarks of AD and LBD, e.g. cognitive deficits, Abeta & tau pathologies, and alpha-synuclein aggregates.


Conclusions:
The mechanism of action of NSC001 via activation of postsynaptic M1mAChR provides a compelling rationale in support of its cognitive benefits and potential disease-modifying properties in AD and other related CNS diseases. Compared with several muscarinic agonists and M1 positive modulators, NSC001 may also have an improved therapeutic value in later neurodegeneration stages, when ACh release is mostly depleted. NSC001 may become a novel therapy in AD with fast cognitive-enhancing effects paralleled by long-term disease-modifying effects on AD pathology.