Ventral tegmental area disruption in Alzheimer's disease

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In vivo mapping of brainstem nuclei functional connectivity disruption in Alzheimer's disease

We assessed here functional connectivity changes in the locus coeruleus (LC) and ventral tegmental area (VTA) of patients with Alzheimer's disease (AD). We recruited 169 patients with either AD or amnestic mild cognitive impairment due to AD and 37 elderly controls who underwent cognitive and neuropsychiatric assessments and resting-state functional magnetic resonance imaging at 3T. Connectivity was assessed between LC and VTA and the rest of the brain. In amnestic mild cognitive impairment patients, VTA disconnection was predominant with parietal regions, while in AD patients, it involved the posterior nodes of the default-mode network. We also looked at the association between neuropsychiatric symptoms (assessed by the neuropsychiatric inventory) and VTA connectivity. Symptoms such as agitation, irritability, and disinhibition were associated with VTA connectivity with the parahippocampal gyrus and cerebellar vermis, while sleep and eating disorders were associated with VTA connectivity to the striatum and the insular cortex. This suggests a contribution of VTA degeneration to AD pathophysiology and to the occurrence of neuropsychiatric symptoms. We did not find evidence of LC disconnection, but this could be explained by the size of this nucleus, which makes it difficult to isolate. These results are consistent with animal findings and have potential implications for AD prognosis and therapies

Persistent elevation of D-Aspartate enhances NMDA receptor-mediated responses in mouse substantia nigra pars compacta dopamine neurons

Dopamine neurons in the substantia nigra pars compacta regulate not only motor but also cognitive functions. NMDA receptors play a crucial role in modulating the activity of these cells. Considering that the amino-acid D-Aspartate has been recently shown to be an endogenous NMDA receptor agonist, the aim of the present study was to examine the effects of D-Aspartate on the functional properties of nigral dopamine neurons. We compared the electrophysiological actions of D-Aspartate in control and D-aspartate oxidase gene (Ddo(-/-)) knock-out mice that show a concomitant increase in brain D-Aspartate levels, improved synaptic plasticity and cognition. Finally, we analyzed the effects of L-Aspartate, a known dopamine neuron endogenous agonist in control and Ddo(-/-) mice. We show that D- and L-Aspartate excite dopamine neurons by activating NMDA, AMPA and metabotropic glutamate receptors. Ddo deletion did not alter the intrinsic properties or dopamine sensitivity of dopamine neurons. However, NMDA-induced currents were enhanced and membrane levels of the NMDA receptor GluN1 and GluN2A subunits were increased. Inhibition of excitatory amino-acid transporters caused a marked potentiation of D-Aspartate, but not L-Aspartate currents, in Ddo(-/-) neurons. This is the first study to show the actions of D-Aspartate on midbrain dopamine neurons, activating not only NMDA but also non-NMDA receptors. Our data suggest that dopamine neurons, under conditions of high D-Aspartate levels, build a protective uptake mechanism to compensate for increased NMDA receptor numbers and cell hyper-excitation, which could prevent the consequent hyper-dopaminergia in target zones that can lead to neuronal degeneration, motor and cognitive alterations

transient upregulation of translational efficiency in prodromal and early symptomatic tg2576 mice contributes to aβ pathology

Abstract Tg2576 mice show high levels of human APP protein with Swedish Mutation during prodromal and early symptomatic stages. Interestingly, this is strictly associated with unbalanced expression of its two RNA binding proteins (RBPs) regulators, the Fragile-X Mental Retardation Protein (FMRP) and the heteronuclear Ribonucleoprotein C (hnRNP C). Whether an augmentation in overall translational efficiency also contributes to the elevation of APP levels at those early developmental stages is currently unknown. We investigated this possibility by performing a longitudinal polyribosome profiling analysis of APP mRNA and protein in total hippocampal extracts from Tg2576 mice. Results showed that protein polysomal signals were exclusively detected in pre-symptomatic (1 months) and early symptomatic (3 months) mutant mice. Differently, hAPP mRNA polysomal signals were detected at any age, but a peak of expression was found when mice were 3-month old. Consistent with an early but transient rise of translational efficiency, the phosphorylated form of the initial translation factor eIF2α (p-eIF2α) was reduced at pre-symptomatic and early symptomatic stages, whereas it was increased at the fully symptomatic stage. Pharmacological downregulation of overall translation in early symptomatic mutants was then found to reduce hippocampal levels of full length APP, Aβ species, BACE1 and Caspase-3, to rescue predominant LTD at hippocampal synapses, to revert dendritic spine loss and memory alterations, and to reinstate memory-induced c-fos activation. Altogether, our findings demonstrate that overall translation is upregulated in prodromal and early symptomatic Tg2576 mice, and that restoring proper translational control at the onset of AD-like symptoms blocks the emergence of the AD-like phenotype

Passive immunotherapy for N-truncated tau ameliorates the cognitive deficits in two mouse Alzheimer's disease models

Abstract Clinical and neuropathological studies have shown that tau pathology better correlates with the severity of dementia than amyloid plaque burden, making tau an attractive target for the cure of Alzheimer's disease. We have explored whether passive immunization with the 12A12 monoclonal antibody (26–36aa of tau protein) could improve the Alzheimer's disease phenotype of two well-established mouse models, Tg2576 and 3xTg mice. 12A12 is a cleavage-specific monoclonal antibody which selectively binds the pathologically relevant neurotoxic NH226-230 fragment (i.e. NH2htau) of tau protein without cross-reacting with its full-length physiological form(s). We found out that intravenous administration of 12A12 monoclonal antibody into symptomatic (6 months old) animals: (i) reaches the hippocampus in its biologically active (antigen-binding competent) form and successfully neutralizes its target; (ii) reduces both pathological tau and amyloid precursor protein/amyloidβ metabolisms involved in early disease-associated synaptic deterioration; (iii) improves episodic-like type of learning/memory skills in hippocampal-based novel object recognition and object place recognition behavioural tasks; (iv) restores the specific up-regulation of the activity-regulated cytoskeleton-associated protein involved in consolidation of experience-dependent synaptic plasticity; (v) relieves the loss of dendritic spine connectivity in pyramidal hippocampal CA1 neurons; (vi) rescues the Alzheimer's disease-related electrophysiological deficits in hippocampal long-term potentiation at the CA3-CA1 synapses; and (vii) mitigates the neuroinflammatory response (reactive gliosis). These findings indicate that the 20–22 kDa NH2-terminal tau fragment is crucial target for Alzheimer's disease therapy and prospect immunotherapy with 12A12 monoclonal antibody as safe (normal tau-preserving), beneficial approach in contrasting the early Amyloidβ-dependent and independent neuropathological and cognitive alterations in affected subjects

Meccanismi molecolari coinvolti nella degenerazione sinaptica in un modello murino di malattia di Alzheimer

La Malattia di Alzheimer è un malattia neurodegenerativa e progressiva per la quale sono stati generati diversi modelli animali. Un numero sempre crescente di evidenze dimostra che la disfunzione neuronale si verifica prima della formazione di placche di beta-amiloide e della morte del neurone stesso. In questo lavoro è stato valutato se una precoce attivazione di apoptosi, nelle sinapsi, possa condurre ad una progressiva perdita delle stesse, che è una delle maggiori caratteristiche della condizione del Mild Cognitive Impairment (MCI). E’ stata utilizzata, come modello di malattia, la linea Tg2576 che sovraesprime l’isoforma umana del precursore della beta-amiloide portatrice della mutazione Swedish (mutazione presente in alcune forme familiari della Malattia di Alzheimer). In letteratura è presente che questo modello di malattia, a 6 mesi di età presenta i primi deficit nella memoria spaziale mentre le prime placche di beta-amiloide, sono riscontrabili (in ippocampo e neocorteccia) non prima di 10 mesi di età. Non sono apprezzabili evidenti segni di morte neuronale nel corso della vita dell’animale. Sulla base delle caratteristiche sopra menzionate, questo animale può essere considerato un buon modello di MCI. I nostri risultati evidenziano che la capasi-3, prodotto terminale della cascata apoptica, è molto più attiva nel compartimento post-sinaptico dei neuroni ippocampali di un animale transgenico (tg) rispetto all’animale wild type (wt). Questo dato è coincidente con una riduzione del numero di spine dendritiche nella regione CA1 dell’ippocampo. Con l’obiettivo di confermare, in vitro, il coinvolgimento dell’apoptosi, nella neurodegenerazione beta-amiloide indotta, abbiamo generato un modello di neuroni primari. Il modello consiste di neuroni primari dissezionati da embrioni transgenici per la beta-amiloide ma privi della proteina Apaf1, che svolge un ruolo chiave nell’apoptosi mitocondrio-mediata. I risultati dimostrano che i neuroni transgenici hanno più caspasi-3 attiva che i neuroni wt e che l’attivazione della caspasi-3 è completamente abolita in assenza della proteina Apaf1. E’ stato, altresì, analizzato lo stress ossidativo, noto essere rilevante nella progressione della malattia, nell’ippocampo di animali wt e tg. I dati presentati in questo lavoro dimostrano che la caspasi-3 svolge un importante ruolo nei processi di degenerazione sinaptica caratteristica della fase iniziale della Malattia di Alzheimer. Questo studio potrebbe portare all’identificazione di nuovi target terapeutici che rallentano i processi neurodegenerativi nella fase iniziale di malattia.Alzheimer Disease (AD) is a progressive neurodegenerative disorder for which numerous mouse models have been generated. A growing body of evidence demonstrate that neuronal dysfunction occurs before Aβ-plaques deposition and neuronal death. We evaluated if an early apoptotic activation at the synapses can lead to a progressive synapse degeneration and to a progressive loss of neuronal connectivity, which is a major clinical feature of a first phase of AD, referred to as Mild Cognitive Impairment (MCI). We used, as a mouse model of AD, the Tg2576 strain, which expresses an amyloid precursor protein (APP695) harboring the Swedish familial AD mutation. It has been demonstrated that, in this mouse model, the spatial memory impairment, evaluated in Morris water maze, could be detected at the age of 6 months; noteworthy, at 10 months of age, only a few senile plaques are detected in several brain regions, including the cortex and hippocampus. Therefore, this transgenic mouse line, at an early stage, could be considered as a model for MCI. Our results highlight that the apoptosis molecules are much more active in the transgenic mouse than in non-transgenic littermates at a very early stage (3 months) in hippocampal neuron synapses. These findings are coincident with a decreased spine density in the radium stratum of the CA1 region of hippocampus. In order to verify the impairment of apoptosis in Aβ-induced neurodegeneration we generated a novel cellular model. This consists of primary neuron dissected from perinatal double transgenic individuals (apoptosome-deficient by Apaf-1 inactivation expressing the human mutated APP transgene). We are evaluating if the reduction of dendritic spine number is depedent on caspase cleavage of post synaptic proteins and if the apoptosome is involved in this pathway. Moreover, we analyzed the oxidative damage, known to be relevant in the progression of the disease. It is still unclear whether, in the early stages of AD, oxidative stress precedes and contributes directly to AD pathogenesis, both in hippocampal synapses in vivo and in primary neurons from the Tg2576 mouse model. This study could lead to the identification of new therapeutical targets to slow down the neurodegenerative process in its early phase