Periodic dietary restriction ameliorates amyloid pathology and cognitive impairment in PDAPP-J20 mice: Potential implication of glial autophagy

NEUROBIOLOGY OF DISEASE

卷:132

Article

Gregosa, Aural^1,2,3  Vinuesa, Angeles^1,2  Florencia Todero, Maria⁴  Pomilio, Carlos^1,2  Rossi, Soledad P.^1,5  Bentivegna, Melisa^1,2  Presa, Jessica^1,2  Wenker, Shirley⁶  Saravia, Flavia^1,2  Beauquis, Juan^1,2 

[1] Consejo Nacl Invest Cient & Tecn, Inst Biol & Med Expt, Buenos Aires, DF, Argentina

[2] Univ Buenos Aires, Fac Ciencias Exactas & Nat, Dept Quim Biol, Buenos Aires, DF, Argentina

[3] Univ Buenos Aires, Fac Farmacia & Bioquim, Catedra Anat & Histol, Buenos Aires, DF, Argentina

[4] Acad Nacl Med Buenos Aires, CONICET, Inst Med Expt IMEX, Lab Fisiol Proc Inflamatorios, Buenos Aires, DF, Argentina

[5] Univ Buenos Aires, Fac Med, Catedra Bioquim Humana, Buenos Aires, DF, Argentina

[6] Consejo Nacl Invest Cient & Tecn, Fdn Inst Leloir IIBA, Buenos Aires, DF, Argentina

关键词: Alzheimer's disease;    Nutrient restriction;    Memory;    Amyloid;    Astroglia;    Autophagy;   

DOI  :  10.1016/j.nbd.2019.104542

来源: Elsevier

【 摘 要 】

Dietary restriction promotes cell regeneration and stress resistance in multiple models of human diseases. One of the conditions that could potentially benefit from this strategy is Alzheimer's disease, a chronic, progressive and prevalent neurodegenerative disease. Although there are no effective pharmacological treatments for this pathology, lifestyle interventions could play therapeutic roles. Our objectives were 1) to evaluate the effects of dietary restriction on cognition, hippocampal amyloid deposition, adult neurogenesis and glial reactivity and autophagy in a mouse model of familial Alzheimer's disease, and 2) to analyze the role of glial cells mediating the effects of nutrient restriction in an in vitro model. Therefore, we established a periodic dietary restriction protocol in adult female PDAPP-J20 transgenic mice for 6 weeks. We found that dietary restriction, not involving overall caloric restriction, attenuated cognitive deficits, amyloid pathology and microglial reactivity in transgenic mice when compared with ad libitum-fed transgenic animals. Also, transgenic mice showed an increase in the astroglial positive signal for LC3, an autophagy-associated protein. In parallel, hippocampal adult neurogenesis was decreased in transgenic mice whereas dietary-restricted transgenic mice showed a neurogenic status similar to controls. In vitro experiments showed that nutrient restriction decreased astroglial and, indirectly, microglial NF kappa B activation in response to amyloid beta peptides. Furthermore, nutrient restriction was able to preserve astroglial autophagic flux and to decrease intracellular amyloid after exposure to amyloid 13 peptides. Our results suggest neuroprotective effects of nutrient restriction in Alzheimer's disease, with modulation of glial activation and autophagy being potentially involved pathways.

【 授权许可】

Free