Propranolol restores cognitive deficits and improves amyloid and Tau pathologies in a senescence-accelerated mouse model

• Published in: Neuropharmacology 2013-01, Vol.64, p.137-144
• Main Authors: Dobarro, Marta, Orejana, Lourdes, Aguirre, Norberto, Ramírez, María Javier
• Format: Article
• Language: English
• Subjects: Adrenergic beta-Antagonists - therapeutic use; Ageing; Aging; Amyloid Neuropathies - drug therapy; Amyloid Neuropathies - physiopathology; Animals; Antihypertensive Agents - therapeutic use; Aβ levels; BACE1; Biomarkers - metabolism; Cognition Disorders - etiology; Cognition Disorders - prevention & control; Disease Models, Animal; Hippocampus; Hippocampus - drug effects; Hippocampus - growth & development; Hippocampus - metabolism; IDE; JNK1; Male; Memory Disorders - etiology; Memory Disorders - prevention & control; Mice; Mice, Inbred Strains; Neuronal Plasticity - drug effects; Neurons - drug effects; Neurons - metabolism; Nootropic Agents - therapeutic use; Phosphorylation - drug effects; Propranolol - therapeutic use; Protein Processing, Post-Translational - drug effects; Random Allocation; SAMP8; tau Proteins - metabolism; Tauopathies - drug therapy; Tauopathies - physiopathology
• ISSN: 0028-3908; 1873-7064
• DOI: 10.1016/j.neuropharm.2012.06.047

Ageing is associated with a deterioration of cognitive performance and with increased risk of neurodegenerative disorders. Hypertension is the most-prevalent modifiable risk factor for cardiovascular morbidity and mortality worldwide, and clinical data suggest that hypertension is a risk factor for Alzheimer's disease (AD). In the present study we tested whether propranolol, a β-receptor antagonist commonly used as antihypertensive drug, could ameliorate the cognitive impairments and increases in AD-related markers shown by the senescence-accelerated mouse prone-8 (SAMP8). Propranolol administration (5 mg/kg for 3 weeks) to 6-month-old SAMP8 mice attenuated cognitive memory impairments shown by these mice in the novel object recognition test. In the hippocampus of SAMP8 mice it has been found increases in Aβ42 levels, the principal constituent of amyloid plaques observed in AD, accompanied by both an increased expression of the cleaving enzyme BACE1 and a decreased expression of the degrading enzyme IDE. All these effects were reversed by propranolol treatment. Tau hyperphosphorylation (PHF-1 epitope) shown by SAMP8 mice at this age was also decreased in the hippocampus of propranolol-treated mice, an effect probably related to a decrease in JNK1 expression. Interestingly, propranolol also phosphorylated Akt in SAMP8 mice, which was associated with an increase of glycogen synthase kinase-3β phosphorylation, contributing therefore to the reductions in Tau hyperphosphorylation. Synaptic pathology in SAMP8 mice, as shown by decreases in synaptophysin and BDNF, was also counteracted by propranolol treatment. Overall, propranolol might be beneficial in age-related brain dysfunction and could be an emerging candidate for the treatment of other neurodegenerative diseases. This article is part of a Special Issue entitled ‘Cognitive Enhancers’. ► Propranolol attenuated cognitive memory impairments in SAMP8 mice in NORT. ► SAMP8 show increases in Aβ42 levels and BACE1 expression and decreased IDE expression. ► Increases in pTau related to a decrease in JNK1 expression were shown by SAMP8 mice. ► SAMP8 mice displayed synaptic pathology, as shown by decreases in synaptophysin and BDNF. ► Amyloid, Tau and synaptic pathology in SAMP8 mice all reversed by propranolol.