Clearing Amyloid-β through PPARγ/ApoE Activation by Genistein is a Treatment of Experimental Alzheimer’s Disease

Article type: Research Article

Authors: Bonet-Costa, Vicent^a | Herranz-Pérez, Vicente^{b; c} | Blanco-Gandía, MariCarmen^d | Mas-Bargues, Cristina^a | Inglés, Marta^e | Garcia-Tarraga, Patricia^b | Rodriguez-Arias, Marta^d | Miñarro, Jose^d | Borras, Consuelo^{a; *} | Garcia-Verdugo, Jose Manuel^{b; c} | Viña, Jose^{a; *}

Affiliations: [a] Department of Physiology, Faculty of Medicine, University of Valencia/INCLIVA, Valencia, Spain | [b] Laboratory of Comparative Neurobiology, Institute Cavanilles, University of Valencia, CIBERNED, Valencia, Spain | [c] Multiple sclerosis and Neuro-regeneration mixed unit, IIS Hospital La Fe, Valencia, Spain | [d] Department of Psychobiology, Faculty of Psychology, University of Valencia, Valencia, Spain | [e] Department of Physiotherapy, Faculty of Physiotherapy, University of Valencia, Valencia, Spain

Correspondence: [*] Correspondence to: Jose Viña, MD, PhD, and ConsueloBorras, PhD, Department of Physiology, Faculty of Medicine, Avenida Blasco Ibañez 15, 46010 Valencia, Spain. Tel.: +34 963 864 646; Fax: +34 963 864 642; E-mails: jose.vina@uv.es (J. Viña) and consuelo.borras@uv.es (C. Borras).

Abstract: Amyloid-β (Aβ) clearance from brain, which is decreased in Alzheimer’s disease, is facilitated by apolipoprotein E (ApoE). ApoE is upregulated by activation of the retinoid X receptor moiety of the RXR/PPARγ dimeric receptor. Genistein, a non-toxic, well-tested, and inexpensive drug activates the other moiety of the receptor PPARγ. Treatment of an Alzheimer’s disease mouse model with genistein results in a remarkable and rapid improvement in various parameters of cognition, such as hippocampal learning, recognition memory, implicit memory, and odor discrimination. This is associated with a lowering of Aβ levels in brain, in the number and the area of amyloid plaques (confirmed in vivo by positron emission tomography) as well as in microglial reactivity. Finally, incubation of primary astrocytes with genistein results in a PPARγ-mediated increased release of ApoE. Our results strongly suggest that controlled clinical trials should be performed to test the effect of genistein as treatment of human Alzheimer’s disease.

Keywords: Aging, biomedical research, neurodegenerative disease, neuroscience, phytoestrogens

DOI: 10.3233/JAD-151020

Journal: Journal of Alzheimer's Disease, vol. 51, no. 3, pp. 701-711, 2016