Early treatment with an M1 and sigma-1 receptor agonist prevents cognitive decline in a transgenic rat model displaying Alzheimer-like amyloid pathology

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作   者：

Orciani, Chiara;  Do Carmo, Sonia;  Foret, Morgan K.;  Hall, Helene;  Lavagna, Agustina;  Bonomo, Quentin;  Huang, Chunwei;  Cuello, A. Claudio; 

关键词：

BDNF MESSENGER-RNA;  OXIDATIVE STRESS;  NEUROTROPHIC FACTOR;  IFN-GAMMA;  MORRIS WATER MAZE;  Neuroinflammation;  Sigma-1 receptor;  MUSCARINIC ACETYLCHOLINE-RECEPTORS;  NERVE GROWTH-FACTOR;  CHOLINERGIC NEURONS;  HUMAN-BRAIN;  Amyloid pathology;  BASAL FOREBRAIN;  Alzheimer's disease;  Muscarinic agonist; 

期刊名称：

Neurobiology of Aging: Experimental and Clinical Research

i s s n：

0197-4580

年卷期：

2023 年 132 卷

页   码：

220-232

页   码：

摘   要：

The application of the selective allosteric M1 muscarinic and sigma-1 receptor agonist, AF710B (aka ANAVEX3-71), has shown to attenuate Alzheimer's disease-like hallmarks in McGill-R-Thy1-APP transgenic rats when administered at advanced pathological stages. It remains unknown whether preventive treatment strategies applying this compound may be equally effective. We tested whether daily oral administration of AF710B (10 mu g/kg) in 7-month-old, preplaque, McGill-R-Thy1-APP rats for 7 months, followed by a 4-week washout period, could prevent Alzheimer's disease-like pathological hallmarks. Long-term AF710B treat-ment prevented the cognitive impairment of McGill-R-Thy1-APP rats. The effect was accompanied by a reduction in the number of amyloid plaques in the hippocampus and the levels of A beta 42 and A beta 40 peptides in the cerebral cortex. AF710B treatment also reduced microglia and astrocyte recruitment toward CA1 hip-pocampal A beta-burdened neurons compared to vehicle-treated McGill-R-Thy1-APP rats, also altering the in-flammatory cytokines profile. Lastly, AF710B treatment rescued the conversion of brain-derived neurotrophic factor precursor to its mature and biologically active form. Overall, these results suggest preventive and disease-modifying properties of the compound. (c) 2023 Elsevier Inc. All reserved.