Liver X Receptors ligand and Minocycline: effectiveness of combined drug therapy in an Alzheimer's transgenic mouse model

MARTIN A. BRUNO , VALERIA FLAQUE; AND A. CLAUDIO CUELLO

Vancouver

Congreso; International Congress of Alzheimer disease; 2012

Alzheimer Association International

Background: Alzheimer´s disease (AD) is a multifactorial disorder (combination of genes and environmental factors) and apparently involves several different etiopathogenic mechanisms. Currently, there is no effective treatment to halt the progression or prevent the onset of AD. A number of theories involving various risk factors such as diet, lifestyle, socioeconomic status, genetic predisposition and head injury have been proposed, but the degree of contribution of each factor is still controversial. Along with age, several factors appear to be widely acknowledged as early risk factors for development of AD including chronic neuroinflammation, brain oxidative damage, hypercholesterolemia and Apolipoprotein E. On the other hand, there is a solid body of scientific evidence that the progressive brain accumulation of the peptide Abeta is key to the AD neuropathology. In recent studies, the initiation and progression of AD has been linked to neuroinflammation, cholesterol metabolism (including APOE activity) and Abeta accumulation, processes that can be modulated by minocycline and liver x receptors (LXRs). environmental factors) and apparently involves several different etiopathogenic mechanisms. Currently, there is no effective treatment to halt the progression or prevent the onset of AD. A number of theories involving various risk factors such as diet, lifestyle, socioeconomic status, genetic predisposition and head injury have been proposed, but the degree of contribution of each factor is still controversial. Along with age, several factors appear to be widely acknowledged as early risk factors for development of AD including chronic neuroinflammation, brain oxidative damage, hypercholesterolemia and Apolipoprotein E. On the other hand, there is a solid body of scientific evidence that the progressive brain accumulation of the peptide Abeta is key to the AD neuropathology. In recent studies, the initiation and progression of AD has been linked to neuroinflammation, cholesterol metabolism (including APOE activity) and Abeta accumulation, processes that can be modulated by minocycline and liver x receptors (LXRs). Alzheimer´s disease (AD) is a multifactorial disorder (combination of genes and environmental factors) and apparently involves several different etiopathogenic mechanisms. Currently, there is no effective treatment to halt the progression or prevent the onset of AD. A number of theories involving various risk factors such as diet, lifestyle, socioeconomic status, genetic predisposition and head injury have been proposed, but the degree of contribution of each factor is still controversial. Along with age, several factors appear to be widely acknowledged as early risk factors for development of AD including chronic neuroinflammation, brain oxidative damage, hypercholesterolemia and Apolipoprotein E. On the other hand, there is a solid body of scientific evidence that the progressive brain accumulation of the peptide Abeta is key to the AD neuropathology. In recent studies, the initiation and progression of AD has been linked to neuroinflammation, cholesterol metabolism (including APOE activity) and Abeta accumulation, processes that can be modulated by minocycline and liver x receptors (LXRs). Methods: This study is aimed to test the effectiveness of the combined daily administration of minocycline with LXRs agonist (during four weeks) to establish the extent of the benefits of the combined therapy (synergism), as opposed to monotherapy with the two above-mentioned agents in our AD-like transgenic mouse model coded McGill-Thy1-APP. minocycline with LXRs agonist (during four weeks) to establish the extent of the benefits of the combined therapy (synergism), as opposed to monotherapy with the two above-mentioned agents in our AD-like transgenic mouse model coded McGill-Thy1-APP. This study is aimed to test the effectiveness of the combined daily administration of minocycline with LXRs agonist (during four weeks) to establish the extent of the benefits of the combined therapy (synergism), as opposed to monotherapy with the two above-mentioned agents in our AD-like transgenic mouse model coded McGill-Thy1-APP. Results: we have been able to demonstrate and replicate the known beneficial CNS effects of minocycline treatment as an antioxidant and anti-inflammatory agent in our transgenic AD mouse model. Moreover, we have confirmed that Liver X receptor (LXRs) agonists? treatment in our AD transgenic mouse model reverse cognitive deficits and facilitated the proteolytic degradation of Abeta, without inducing hepatic steatosis and hypertriglyceridemia . When combined, animals receiving both agents simultaneously, displayed a marked reduction of cortical peroxynitritemediated oxidative damage, lowered burden of Aâ and decreased pro-inflammatory markers (IL- 1â). oxidative damage, lowered burden of Aâ and decreased pro-inflammatory markers (IL- 1â). minocycline treatment as an antioxidant and anti-inflammatory agent in our transgenic AD mouse model. Moreover, we have confirmed that Liver X receptor (LXRs) agonists? treatment in our AD transgenic mouse model reverse cognitive deficits and facilitated the proteolytic degradation of Abeta, without inducing hepatic steatosis and hypertriglyceridemia . When combined, animals receiving both agents simultaneously, displayed a marked reduction of cortical peroxynitritemediated oxidative damage, lowered burden of Aâ and decreased pro-inflammatory markers (IL- 1â). oxidative damage, lowered burden of Aâ and decreased pro-inflammatory markers (IL- 1â). we have been able to demonstrate and replicate the known beneficial CNS effects of minocycline treatment as an antioxidant and anti-inflammatory agent in our transgenic AD mouse model. Moreover, we have confirmed that Liver X receptor (LXRs) agonists? treatment in our AD transgenic mouse model reverse cognitive deficits and facilitated the proteolytic degradation of Abeta, without inducing hepatic steatosis and hypertriglyceridemia . When combined, animals receiving both agents simultaneously, displayed a marked reduction of cortical peroxynitritemediated oxidative damage, lowered burden of Aâ and decreased pro-inflammatory markers (IL- 1â). oxidative damage, lowered burden of Aâ and decreased pro-inflammatory markers (IL- 1â). mediated oxidative damage, lowered burden of Aâ and decreased pro-inflammatory markers (IL- 1â). Conclusion: This preliminary study provides evidence of the benefits of the combined therapy (synergism), as opposed to monotherapy with minocycline and LXRs agonist in our AD-like transgenic mouse model. These observations suggest that the combined administration may represent a promising therapeutic opportunity. Acknowledgements: this work is supported by Agencia FONCyT Argentina (PICT 2008-1989) to MAB and CIHR grant MOP219489 to ACC. Agencia FONCyT Argentina (PICT 2008-1989) to MAB and CIHR grant MOP219489 to ACC. (synergism), as opposed to monotherapy with minocycline and LXRs agonist in our AD-like transgenic mouse model. These observations suggest that the combined administration may represent a promising therapeutic opportunity. Acknowledgements: this work is supported by Agencia FONCyT Argentina (PICT 2008-1989) to MAB and CIHR grant MOP219489 to ACC. Agencia FONCyT Argentina (PICT 2008-1989) to MAB and CIHR grant MOP219489 to ACC. This preliminary study provides evidence of the benefits of the combined therapy (synergism), as opposed to monotherapy with minocycline and LXRs agonist in our AD-like transgenic mouse model. These observations suggest that the combined administration may represent a promising therapeutic opportunity. Acknowledgements: this work is supported by Agencia FONCyT Argentina (PICT 2008-1989) to MAB and CIHR grant MOP219489 to ACC. Agencia FONCyT Argentina (PICT 2008-1989) to MAB and CIHR grant MOP219489 to ACC. Acknowledgements: this work is supported by Agencia FONCyT Argentina (PICT 2008-1989) to MAB and CIHR grant MOP219489 to ACC.