Vanessa De Castro

Abnormal accumulation of autophagic vesicles correlates with axonal and synaptic pathology in young Alzheimer’s mice hippocampus

Dystrophic neurites associated with amyloid plaques precede neuronal death and manifest early in Alzheimer’s disease (AD). In this work we have characterized the plaque-associated neuritic pathology in the hippocampus of young (4- to 6-month-old) PS1M146L/APP751SL mice model, as the initial degenerative process underlying functional disturbance prior to neuronal loss. Neuritic plaques accounted for almost all fibrillar deposits and an axonal origin of the dystrophies was demonstrated. The early induction of autophagy pathology was evidenced by increased protein levels of the autophagosome marker LC3 that was localized in the axonal dystrophies, and by electron microscopic identification of numerous autophagic vesicles filling and causing the axonal swellings. Early neuritic cytoskeletal defects determined by the presence of phosphorylated tau (AT8-positive) and actin–cofilin rods along with decreased levels of kinesin-1 and dynein motor proteins could be responsible for this extensive vesicle accumulation within dystrophic neurites. Although microsomal Aβ oligomers were identified, the presence of A11-immunopositive Aβ plaques also suggested a direct role of plaque-associated Aβ oligomers in defective axonal transport and disease progression. Most importantly, presynaptic terminals morphologically disrupted by abnormal autophagic vesicle buildup were identified ultrastructurally and further supported by synaptosome isolation. Finally, these early abnormalities in axonal and presynaptic structures might represent the morphological substrate of hippocampal dysfunction preceding synaptic and neuronal loss and could significantly contribute to AD pathology in the preclinical stages.

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

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.

Efectos de la administración de (RS)-3,4-DCPG, un antagonista mixto de los receptores AMPA y agonista de los receptores mGlu8, en la conducta agresiva de los ratones

INTRODUCTION Ionotropic and metabotropic (mGlu) receptors of glutamate have been suggested to be involved in the modulation of aggression. Thus, recent studies found reduced aggression in AMPA-type glutamate receptor GluR-A subunit-deficient mice. Likewise, mGlu1 and 5 receptors have also been implicated in aggression regulation. (RS)-3,4-DCPG is a mixed antagonist of AMPA receptors and an agonist of mGluR8. The AMPA antagonist activity of this compound is determined by its R isomer while the S isomer is responsible for its mGluR8 agonistic properties. METHODS We analyzed the effects of (RS)-3,4-DCPG (5, 10 and 20mg/kg, ip) on agonistic encounters between male mice. Individually housed mice were exposed to anosmic opponents 30 min after drug administration. Ten min of dyadic interactions were staged between a singly housed and an anosmic mouse in a neutral area. The encounters were videotaped and the accumulated time allocated by subjects to 10 broad behavioral categories was estimated using an ethologically based analysis. RESULTS AND CONCLUSIONS The results indicated that (RS)-3,4-DCPG produced no significant behavioral changes, suggesting that antagonism of AMPA receptors by the R isomer and stimulation of mGluR8 by the S isomer do not act synergistically on aggression in the racemic form of 3,4-DCPG.

Axonal neuritic pathology induces early presynaptic alterations in ps1/APP Alzheimer's mice hippocampus

Loss of neurons in the hippocampus correlates with memory impairment in AD. Significant early reduction in the numerical density of hippocampal SOM interneurons was found in single (APPswe) and double (APPswe/ PS1dE9 and APPswe/TauP301S-G272V) transgenic models based on APP over expression and amyloid production. However, this inhibitory population was unaffected in age-matched single PS1 and tau transgenic mice as well as nontransgenic controls. Whereas SOM neuron loss in APPswe/PS1dE9 was associated to the onset of extracellular amyloid pathology in double APP/ tau mice this loss preceded plaque formation. Conclusions: As in human AD, somatostatin cell loss is a common early pathological feature in the hippocampus of different single and double transgenic mice strains harboring APP mutations. Amyloid plaques alone do not account for this selective neuronal degeneration and most likely soluble oligomeric amyloid peptides are the primary causative agent. Finally, the vulnerability of these interneurons may have substantial functional repercussions on local inhibitory processes and memory function in the hippocampus.