In vivo modification of Abeta plaque toxicity as a novel neuroprotective lithium-mediated therapy for Alzheimer’s disease pathology

Abstract

BackgroundAlzheimer’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.ResultsThough 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.ConclusionsOur 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.

Phagocytic clearance of presynaptic dystrophies by reactive astrocytes in Alzheimer's disease

“…As expected (Jimenez et al, 2008; Serrano‐Pozo, Muzikansky, et al, 2013; Serrano‐Pozo, Betensky, Frosch, & Hyman, 2016; Trujillo‐Estrada et al, 2013), the hippocampus of both the transgenic APP/PS1 model and Alzheimer's patients (Braak V–VI) displays significant astrogliosis (measured by GFAP expression and by the area covered by the reactive astrocytes; see also Jimenez et al, 2008), which progresses in parallel to the extracellular amyloid pathology. The increase in astrocytic reactivity involves both morphological (enlarged cell body and processes) and molecular changes (Osborn et al, 2016).…”

Comparing the effect of the novel ionic cocrystal of lithium salicylate proline (LISPRO) with lithium carbonate and lithium salicylate on memory and behavior in female APPswe/PS1dE9 Alzheimer's mice

“…Our study confirms previous studies showing a beneficial effect of lithium in animal models of AD and AD patients, while also highlighting the potential benefit of LISPRO. Although a few studies reported no effect of lithium chloride on Aβ levels (Caccamo, Oddo, Tran, & LaFerla, ; Feyt et al, ) or even neurodegeneration induced by tau suppression (Lei et al, ), the overriding evidence indicates that lithium treatment effectively reduces extracellular β‐amyloid (Habib et al, ; Trujillo‐Estrada et al, ) and tau hyperphosphorylation in cell culture and animal models of AD (Nery et al, ). Likewise, intracerebroventricular injection of Aβ in zebrafish embryo impairs cognition which was successfully reversed by lithium administration (Nery et al, ).…”

Early Neuronal Loss and Axonal/Presynaptic Damage is Associated with Accelerated Amyloid-β Accumulation in AβPP/PS1 Alzheimer's Disease Mice Subiculum

“…Therefore, the characterization of plaques on the basis of their capacity to induce axonal and neuronal damage is crucial to validate animal models for research and drug testing. In this sense, our A␤PP/PS1 model is of great interest since these mice develop human-like neuritic plaques whose toxicity can be modulated in vivo, as we have recently shown, by lithium administration resulting in a marked reduc-tion of neuronal and axonal damage and cognitive improvement [66].…”