Region-specific changes in the microanatomy of single dendritic spines over time might account for selective memory alterations in ageing hAPPsweTg2576 mice, a mouse model for Alzheimer disease.

Tg2576 mice over-expressing human mutant APP (hAPPswe) show progressive impairments in hippocampal plasticity and episodic memory while fronto-striatal plasticity and procedural memory remain intact. Here we examine the status of synaptic connectivity in the hippocampus and the dorsolateral striatum (DLS) of 3- and 15-month-old Tg2576 and wild-type mice through the analysis of single dendritic spines microanatomy. We found that, in each region, all mice showed a global reduction in the size of spines as a function of age. Ageing mutants, however, exhibited smaller spines with shorter necks on CA1 pyramidal neurons but larger spines with longer necks on DLS spiny neurons compared to their age-matched wild-type controls. Our findings indicate that hippocampal and DLS dendritic spines in hAPPswe mutants undergo a different pattern of morphological changes over time and point to minor alterations in the microanatomy of DLS spines as a compensatory mechanism maintaining procedural abilities in the ageing mutants.

AD-Related N-Terminal Truncated Tau Is Sufficient to Recapitulate In Vivo the Early Perturbations of Human Neuropathology: Implications for Immunotherapy.

The NH2tau 26-44 aa (i.e., NH2htau) is the minimal biologically active moiety of longer 20-22-kDa NH2-truncated form of human tau-a neurotoxic fragment mapping between 26 and 230 amino acids of full-length protein (htau40)-which is detectable in presynaptic terminals and peripheral CSF from patients suffering from AD and other non-AD neurodegenerative diseases. Nevertheless, whether its exogenous administration in healthy nontransgenic mice is able to elicit a neuropathological phenotype resembling human tauopathies has not been yet investigated. We explored the in vivo effects evoked by subchronic intracerebroventricular (i.c.v.) infusion of NH2htau or its reverse counterpart into two lines of young (2-month-old) wild-type mice (C57BL/6 and B6SJL). Six days after its accumulation into hippocampal parenchyma, significant impairment in memory/learning performance was detected in NH2htau-treated group in association with reduced synaptic connectivity and neuroinflammatory response. Compromised short-term plasticity in paired-pulse facilitation paradigm (PPF) was detected in the CA3/CA1 synapses from NH2htau-impaired animals along with downregulation in calcineurin (CaN)-stimulated pCREB/c-Fos pathway(s). Importantly, these behavioral, synaptotoxic, and neuropathological effects were independent from the genetic background, occurred prior to frank neuronal loss, and were specific because no alterations were detected in the control group infused with its reverse counterpart. Finally, a 2.0-kDa peptide which biochemically and immunologically resembles the injected NH2htau was endogenously detected in vivo, being present in hippocampal synaptosomal preparations from AD subjects. Given that the identification of the neurotoxic tau species is mandatory to develop a more effective tau-based immunological approach, our evidence can have important translational implications for cure of human tauopathies.

Progressive cognitive decline in a transgenic mouse model of Alzheimer's disease overexpressing mutant hAPPswe.

The possibility of detecting progressive changes in cognitive function reflecting the spatio-temporal pattern of beta-amyloid peptide (Abeta) deposition was investigated in Tg2576 mice overexpressing the human mutant amyloid precursor protein (hAPP). Here, we show that at 7 months of age, Tg2576 mice exhibited a selective deficit in hippocampus-based operations including a defective habituation of object exploration, a lack of reactivity to spatial novelty and a disruption of allothetic orientation in a cross-shaped maze. At 14 months of age, Tg2576 mice displayed a more extended pattern of behavioral abnormalities, because they failed to react to object novelty and exclusively relied on motor-based orientation in the cross-shaped maze. However, an impaired reactivity to spatial and object novelty possibly reflecting age-related attention deficits also emerged in aged wild-type mice. These findings further underline that early cognitive markers of AD can be detected in Tg2576 mice before Abeta deposition occurs and suggest that as in humans, cognitive deterioration progressively evolves from an initial hippocampal syndrome to global dementia because of the combined effect of the neuropathology and aging.

Free D-aspartate regulates neuronal dendritic morphology, synaptic plasticity, gray matter volume and brain activity in mammals.

D-aspartate (D-Asp) is an atypical amino acid, which is especially abundant in the developing mammalian brain, and can bind to and activate N-methyl-D-Aspartate receptors (NMDARs). In line with its pharmacological features, we find that mice chronically treated with D-Asp show enhanced NMDAR-mediated miniature excitatory postsynaptic currents and basal cerebral blood volume in fronto-hippocampal areas. In addition, we show that both chronic administration of D-Asp and deletion of the gene coding for the catabolic enzyme D-aspartate oxidase (DDO) trigger plastic modifications of neuronal cytoarchitecture in the prefrontal cortex and CA1 subfield of the hippocampus and promote a cytochalasin D-sensitive form of synaptic plasticity in adult mouse brains. To translate these findings in humans and consistent with the experiments using Ddo gene targeting in animals, we performed a hierarchical stepwise translational genetic approach. Specifically, we investigated the association of variation in the gene coding for DDO with complex human prefrontal phenotypes. We demonstrate that genetic variation predicting reduced expression of DDO in postmortem human prefrontal cortex is mapped on greater prefrontal gray matter and activity during working memory as measured with MRI. In conclusion our results identify novel NMDAR-dependent effects of D-Asp on plasticity and physiology in rodents, which also map to prefrontal phenotypes in humans.

Landmark-based but not vestibular-based orientation elicits mossy fiber synaptogenesis in the mouse hippocampus.

This study tries to shed light on the paradoxical finding that two inbred strains of mice C57BL/6 (C57) and DBA/2 (DBA), with differences in hippocampal function, perform similarly in the water maze (WM). Mice from both strains were trained on WM protocols permitting or preventing the use of vestibular signals. Hippocampal involvement in performance was then assessed by estimation of post-training mossy fiber (MF) synaptogenesis. We found that C57 and DBA mice performed similarly when both visual and vestibular information were available but only C57 mice exhibited new MF synapses. Disruption of vestibular inputs impaired performance in DBA mice but not in C57 mice which still exhibited a post-training increase of hippocampal MF synaptic terminals. This strain-specific dissociation indicates that DBA mice can navigate successfully by relying on vestibular signals without engaging their hippocampus. In contrast, vestibular signals are irrelevant for C57 mice since their suppression neither disrupts their behavior nor prevents the formation of new hippocampal synapses. These findings suggest some caution is required in considering performance on standard WM protocols as an index of hippocampus-based learning. Estimating the extent of post-training mossy fiber synaptogenesis would be helpful in solving this issue.