title: In vivo modification of Abeta plaque toxicity as a novel neuroprotective lithium-mediated therapy for Alzheimer's disease pathology.
abstract: BACKGROUND
  Alzheimer's disease (AD) is characterized by the abnormal accumulation of extracellular beta-amyloid (Abeta) plaques, intracellular hyperphosphorylated tau, progressive synaptic alterations, axonal dystrophies, neuronal loss and the deterioration of cognitive capabilities of patients. However, no effective disease-modifying treatment has been yet developed. In this work we have evaluated whether chronic lithium treatment could ameliorate the neuropathology evolution of our well characterized PS1M146LxAPPSwe-London mice model.
  
  
  RESULTS
  Though beneficial effects of lithium have been previously described in different AD models, here we report a novel in vivo action of this compound that efficiently ameliorated AD-like pathology progression and rescued memory impairments by reducing the toxicity of Abeta plaques. Transgenic PS1M146LxAPPSwe-London mice, treated before the pathology onset, developed smaller plaques characterized by higher Abeta compaction, reduced oligomeric-positive halo and therefore with attenuated capacity to induce neuronal damage. Importantly, neuronal loss in hippocampus and entorhinal cortex was fully prevented. Our data also demonstrated that the axonal dystrophic area associated with lithium-modified plaques was highly reduced. Moreover, a significant lower accumulation of phospho-tau, LC3-II and ubiquitinated proteins was detected in treated mice. Our study highlights that this switch of plaque quality by lithium could be mediated by astrocyte activation and the release of heat shock proteins, which concentrate in the core of the plaques.
  
  
  CONCLUSIONS
  Our data demonstrate that the pharmacological in vivo modulation of the extracellular Abeta plaque compaction/toxicity is indeed possible and, in addition, might constitute a novel promising and innovative approach to develop a disease-modifying therapeutic intervention against AD.
authors.affiliation: Departamento de Biologia Celular, Genetica y Fisiologia, Facultad de Ciencias, Universidad de Malaga, 29071 Malaga, Spain. agutierrez@uma.es.
authors.forename: Laura
authors.initials: L
authors.lastname: Trujillo-Estrada
authors.forename: Sebastian
authors.initials: S
authors.lastname: Jimenez
authors.forename: Vanessa
authors.initials: V
authors.lastname: De Castro
authors.forename: Manuel
authors.initials: M
authors.lastname: Torres
authors.forename: David
authors.initials: D
authors.lastname: Baglietto-Vargas
authors.forename: Ines
authors.initials: I
authors.lastname: Moreno-Gonzalez
authors.forename: Victoria
authors.initials: V
authors.lastname: Navarro
authors.forename: Raquel
authors.initials: R
authors.lastname: Sanchez-Varo
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Sanchez-Mejias
authors.forename: Jose Carlos
authors.initials: JC
authors.lastname: Davila
authors.forename: Marisa
authors.initials: M
authors.lastname: Vizuete
authors.forename: Antonia
authors.initials: A
authors.lastname: Gutierrez
authors.forename: Javier
authors.initials: J
authors.lastname: Vitorica
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001253:Astrocytes / Q000187:drug effects / Q000473:pathology / Q000502:physiology; D001921:Brain / Q000187:drug effects* / Q000473:pathology / Q000503:physiopathology; D016923:Cell Death / Q000187:drug effects; D004195:Disease Models, Animal; D006801:Humans; D018020:Lithium Compounds / Q000494:pharmacology*; D008297:Male; D008569:Memory Disorders / Q000188:drug therapy / Q000473:pathology / Q000503:physiopathology; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009474:Neurons / Q000187:drug effects / Q000473:pathology / Q000502:physiology; D018696:Neuroprotective Agents / Q000494:pharmacology*; D058225:Plaque, Amyloid / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D053764:Presenilin-1 / Q000235:genetics / Q000378:metabolism; D011897:Random Allocation
chemical_list: C545487:APP protein, human; D016564:Amyloid beta-Protein Precursor; D018020:Lithium Compounds; D018696:Neuroprotective Agents; C508853:PSEN1 protein, human; D053764:Presenilin-1