Amyloid-ß targeting immunisation in aged non-human primate (Microcebus murinus).

Non-human primates have an important translational value given their close phylogenetic relationship to humans. Studies in these animals remain essential for evaluating efficacy and safety of new therapeutic approaches, particularly in aging primates that display Alzheimer's disease (AD) -like pathology. With the objective to improve amyloid-ß (Aß) targeting immunotherapy, we investigated the safety and efficacy of an active immunisation with an Aß derivative, K6Aß1-30-NH2, in old non-human primates. Thirty-two aged (4-10 year-old) mouse lemurs were enrolled in the study, and received up to four subcutaneous injections of the vaccine in alum adjuvant or adjuvant alone. Even though antibody titres to Aß were not high, pathological examination of the mouse lemur brains showed a significant reduction in intraneuronal Aß that was associated with reduced microgliosis, and the vaccination did not lead to microhemorrhages. Moreover, a subtle cognitive improvement was observed in the vaccinated primates, which was probably linked to Aß clearance. This Aß derivative vaccine appeared to be safe as a prophylactic measure based on the brain analyses and because it did not appear to have detrimental effects on the general health of these old animals.

Reg-1α Promotes Differentiation of Cortical Progenitors via Its N-Terminal Active Domain.

Reg-1α belongs to the Reg family of small, secreted proteins expressed in both pancreas and nervous system. Reg-1α is composed of two domains, an insoluble C-type lectin domain and a short soluble N-terminal peptide, which is released from the molecule upon proteolytic N-terminal processing, although the biological significance of this proteolysis remains unclear. We have previously shown that binding of Reg-1α to its receptor Extl3 stimulates axonal outgrowth. Reg-1α and Extl3 genes are expressed in the developing cortex but their expression decreases in adulthood, pointing to a possible function of this signaling system at the early developmental stages. Here, we demonstrate that recombinant Reg-1α increases migration and differentiation of cultured embryonic rat telencephalic progenitors via the activation of GSK-3ß activity. In vivo overexpression of Reg-1α by in utero electroporation, has a similar effect, favoring premature differentiation of cortical progenitors. Notably, the N-terminal soluble domain, but not the C-type lectin domain, is largely responsible for Reg-1α effects on cortical neuronal differentiation. We thus conclude that Reg-1α via its proteolytically generated N-terminal domain is required for basic development processes.

Linking cognition to age and amyloid-ß burden in the brain of a nonhuman primate (Microcebus murinus).

The gray mouse lemur (Microcebus murinus) is a valuable model in research on age-related proteopathies. This nonhuman primate, comparable to humans, naturally develops tau and amyloid-ß proteopathies during aging. Whether these are linked to cognitive alterations is unknown. Here, standardized cognitive testing in pairwise discrimination and reversal learning in a sample of 37 aged (>5 years) subjects was combined with tau and amyloid-ß histochemistry in individuals that died naturally. Correlation analyses in successfully tested subjects (n = 22) revealed a significant relation between object discrimination learning and age, strongly influenced by outliers, suggesting pathological cases. Where neuroimmunohistochemistry was possible, as subjects deceased, the naturally developed cortical amyloid-ß burden was significantly linked to pretraining success (intraneuronal accumulations) and discrimination learning (extracellular deposits), showing that cognitive (pairwise discrimination) performance in old age predicts the natural accumulation of amyloid-ß at death. This is the first description of a direct relation between the cortical amyloid-ß burden and cognition in a nonhuman primate.

Neuroprotective brain-derived neurotrophic factor signaling in the TAU-P301L tauopathy zebrafish model.

Brain-derived neurotrophic factor (BDNF) dysregulations contribute to the neurotoxicity in neurodegenerative pathologies and could be efficiently targeted by therapies. In Alzheimer's disease (AD), although the relationship between BDNF and amyloid load has been extensively studied, how Tau pathology affects BDNF signaling remains unclear. Using the TAU-P301L transgenic zebrafish line, we investigated how early Tau-induced neurotoxicity modifies BDNF signaling. Alterations in BDNF expression levels were observed as early as 48 h post fertilization in TAU-P301L zebrafish embryos while TrkB receptor expression was not affected. Decreasing BDNF expression, using a knockdown strategy in wild-type embryos to mimic Tau-associated decrease, did not modify TrkB expression but promoted neurotoxicity as demonstrated by axonal outgrowth shortening and neuronal cell death. Moreover, the TrkB antagonist ANA-12 reduced the length of axonal projections. Rescue experiments with exogenous BDNF partially corrected neuronal alterations in TAU-P301L by counteracting primary axonal growth impairment but without effect on apoptosis. Importantly, the axonal rescue was proved functionally effective in a behavioral test, at a similar level as obtained with the GSK3ß inhibitor LiCl, known to decrease TAU phosphorylation. Finally, treatment with a TrkB agonist, 7,8-dihydroxyflavone, led to comparable results and allowed full rescue of locomotor response. We provided here strong evidence that Tau neurotoxicity provoked alterations in BDNF system and that BDNF pathway might represent an efficient therapeutic target.

Associations between long-term adherence to healthy diet and recurrent depressive symptoms in Whitehall II Study.

PURPOSE: We examined whether long-term adherence to three diet quality scores-the Alternative Healthy Eating Index-2010 (AHEI-2010), Dietary Approach to Stop Hypertension (DASH) and  transformed-Mediterranean Diet Score (tMDS), Alternative Healthy Eating Index-2010 (AHEI-2010) and Dietary Approach to Stop Hypertension (DASH) is associated with the risk of recurrent depressive symptoms. METHODS: Analyses were conducted on a sample of 4949 men and women from the Whitehall II study. Diet scores were calculated using data collected from food frequency questionnaires repeated over 11 years of exposure (1991/1993-2002/2004). Recurrence of depressive symptoms was defined when participants reported at least two episodes of depressive symptoms (assessed by Center for Epidemiologic Studies Depression Scale and use of antidepressants) over the four phases of follow-up (2002/04-2015/16). RESULTS: After adjustment for potential cofounders, higher scores on AHEI-2010, DASH and tMDS at the end of the exposure period were associated with lower risk of recurrent depressive symptoms over the 13-year follow-up. Repeat measures of dietary history showed that participants who maintained a high AHEI-2010 score over the 11-year exposure period had a 19% (OR 0.81, 95% CI 0.65-1.00) lower odds of recurrent depressive symptoms compared to those who maintained a low AHEI score. Participants whose AHEI-2010 score decreased over time had a 1.34-fold increased odds (95% CI 1.02-1.75) of developing recurrent depressive symptoms compared to those maintaining a high AHEI-2010. No robust associations were observed for long-term tMDS and DASH. CONCLUSION: Our findings suggest that long-term adherence to healthy diet defined by Alternative Healthy Eating Index-2010 confers protection against recurrent depressive symptoms.

Combining Gene Transfer and Nonhuman Primates to Better Understand and Treat Parkinson's Disease.

Parkinson's disease (PD) is a progressive CNS disorder that is primarily associated with impaired movement. PD develops over decades and is linked to the gradual loss of dopamine delivery to the striatum, via the loss of dopaminergic (DA) neurons in the substantia nigra pars compacta (SNpc). While the administration of L-dopa and deep brain stimulation are potent therapies, their costs, side effects and gradual loss of efficacy underlines the need to develop other approaches. Unfortunately, the lack of pertinent animal models that reproduce DA neuron loss and behavior deficits-in a timeline that mimics PD progression-has hindered the identification of alternative therapies. A complementary approach to transgenic animals is the use of nonhuman primates (NHPs) combined with the overexpression of disease-related genes using viral vectors. This approach may induce phenotypes that are not influenced by developmental compensation mechanisms, and that take into account the personality of animals. In this review article, we discuss the combination of gene transfer and NHPs to develop "genetic" models of PD that are suitable for testing therapeutic approaches.

Regenerating islet-derived 1α (REG-1α) protein increases tau phosphorylation in cell and animal models of tauopathies.

REG-1α, a secreted protein containing a C-type lectin domain, is expressed in various organs and plays different roles in digestive system cells in physiological and pathological conditions. Like other members of the Reg family, REG-1α is expressed also in the brain where it has different functions. For instance, we previously reported that REG-1α regulates neurite outgrowth and is overexpressed during the very early stages of Alzheimer's disease (AD). However, REG-1α function in neural cells during neural degeneration remains unknown. First, REG-1α and phosphorylated tau expression were assessed in tissue sections from the hippocampus, representing neurofibrillary tangles (NFTs), from patients with AD, and from basal ganglia, representing subcortical NFTs, from patients with progressive supranuclear palsy (PSP). We found an association between REG-1α expression, tau hyperphosphorylation and NFTs in human brain samples from patients with these neurodegenerative diseases. Then, the effects of REG-1α overexpression on tau phosphorylation and axonal morphology were investigated i) in primary cultures of rat neurons that express human tau P301L and ii) in a transgenic zebrafish model of tauopathy that expresses human tau P301L. In the tau P301L cell model, REG-1α overexpression increased tau phosphorylation at the S202/T205 and S396 residues (early and late stages of abnormal phosphorylation, respectively) through the AKT/GSK3-ß pathway. This effect was associated with axonal defects both in tau P301L-expressing rat neurons and zebrafish embryos. Our findings suggest a functional role for REG-1α during tauopathy development and progression and, specifically, its involvement in the modification of tau phosphorylation temporal sequence.

Exogenous LRRK2G2019S induces parkinsonian-like pathology in a nonhuman primate.

Parkinson's disease (PD) is the second most prevalent neurodegenerative disease among the elderly. To understand its pathogenesis and to test therapies, animal models that faithfully reproduce key pathological PD hallmarks are needed. As a prelude to developing a model of PD, we tested the tropism, efficacy, biodistribution, and transcriptional effect of canine adenovirus type 2 (CAV-2) vectors in the brain of Microcebus murinus, a nonhuman primate that naturally develops neurodegenerative lesions. We show that introducing helper-dependent (HD) CAV-2 vectors results in long-term, neuron-specific expression at the injection site and in afferent nuclei. Although HD CAV-2 vector injection induced a modest transcriptional response, no significant adaptive immune response was generated. We then generated and tested HD CAV-2 vectors expressing leucine-rich repeat kinase 2 (LRRK2) and LRRK2 carrying a G2019S mutation (LRRK2G2019S), which is linked to sporadic and familial autosomal dominant forms of PD. We show that HD-LRRK2G2019S expression induced parkinsonian-like motor symptoms and histological features in less than 4 months.

Association of Long-Term Diet Quality with Hippocampal Volume: Longitudinal Cohort Study.

BACKGROUND: Diet quality is associated with brain aging outcomes. However, few studies have explored in humans the brain structures potentially affected by long-term diet quality. We examined whether cumulative average of the Alternative Healthy Eating Index 2010 (AHEI-2010) score during adult life (an 11-year exposure period) is associated with hippocampal volume. METHODS: Analyses were based on data from 459 participants of the Whitehall II imaging sub-study (mean age [standard deviation] (SD) = 59.6 [5.3] years in 2002-2004, 19.2% women). Multimodal magnetic resonance imaging examination was performed at the end of follow-up (2015-2016). Structural images were acquired using a high-resolution 3-dimensional T1-weighted sequence and processed with Functional Magnetic Resonance Imaging of the Brain Software Library (FSL) tools. An automated model-based segmentation and registration tool was applied to extract hippocampal volumes. RESULTS: Higher AHEI-2010 cumulative average score (reflecting long-term healthy diet quality) was associated with a larger total hippocampal volume. For each 1 SD (SD = 8.7 points) increment in AHEI-2010 score, an increase of 92.5 mm3 (standard error = 42.0 mm3) in total hippocampal volume was observed. This association was independent of sociodemographic factors, smoking habits, physical activity, cardiometabolic health factors, cognitive impairment, and depressive symptoms, and was more pronounced in the left hippocampus than in the right hippocampus. Of the AHEI-2010 components, no or light alcohol consumption was independently associated with larger hippocampal volume. CONCLUSIONS: Higher long-term AHEI-2010 scores were associated with larger hippocampal volume. Accounting for the importance of hippocampal structures in several neuropsychiatric diseases, our findings reaffirm the need to consider adherence to healthy dietary recommendation in multi-interventional programs to promote healthy brain aging.

Intraocular pressure in the smallest primate aging model: the gray mouse lemur.

OBJECTIVE: The aim of this study was to assess the practicability of common tonometers used in veterinary medicine for rapid intraocular pressure (IOP) screening, to calibrate IOP values gained by the tonometers, and to define a reference IOP value for the healthy eye in a new primate model for aging research, the gray mouse lemur. STUDIED ANIMALS AND PROCEDURES: TonoVet® and the TonoPen™ measurements were calibrated manometrically in healthy enucleated eyes of mouse lemurs euthanized for veterinary reasons. For comparison of the practicability of both tonometers as a rapid IOP assessment tool for living mouse lemurs, the IOP of 24 eyes of 12 animals held in the hand was measured. To define a standard reference value for IOP in mouse lemurs, 258 healthy animals were measured using the TonoVet® . RESULTS: Intraocular pressure measurements for the TonoVet® can be corrected using the formula: y = 0.981 + (1.962*TonoVet® value), and those for the TonoPen™ using that of y = 5.38 + (1.426*TonoPen™ value). The calibrated IOP for a healthy mouse lemur eye was 20.3 ± 2.8 mmHg. The TonoVet® showed advantages in practicability, for example, small corneal contact area, short and painless corneal contact, shortened total time spent on investigation, as well as the more accurate measured values. IOP measurements of healthy mouse lemur eyes were not affected by age, sex, eye side, or colony. CONCLUSION: Tonometry using TonoVet® is the more practicable assessment tool for IOP measurement of the tiny eyes of living mouse lemurs. Pathological deviations can be identified based on the described reference value.

Photoperiodic regime influences onset of lens opacities in a non-human primate.

BACKGROUND: Opacities of the lens are typical age-related phenomena which have a high influence on photoreception and consequently circadian rhythm. In mouse lemurs, a small bodied non-human primate, a high incidence (more than 50% when >seven years) of cataracts has been previously described during aging. Previous studies showed that photoperiodically induced accelerated annual rhythms alter some of mouse lemurs' life history traits. Whether a modification of photoperiod also affects the onset of age dependent lens opacities has not been investigated so far. The aim of this study was therefore to characterise the type of opacity and the mouse lemurs' age at its onset in two colonies with different photoperiodic regimen. METHODS: Two of the largest mouse lemur colonies in Europe were investigated: Colony 1 having a natural annual photoperiodic regime and Colony 2 with an induced accelerated annual cycle. A slit-lamp was used to determine opacities in the lens. Furthermore, a subset of all animals which showed no opacities in the lens nucleus in the first examination but developed first changes in the following examination were further examined to estimate the age at onset of opacities. In total, 387 animals were examined and 57 represented the subset for age at onset estimation. RESULTS: The first and most commonly observable opacity in the lens was nuclear sclerosis. Mouse lemurs from Colony 1 showed a delayed onset of nuclear sclerosis compared to mouse lemurs from Colony 2 (4.35 ± 1.50 years vs. 2.75 ± 0.99 years). For colony 1, the chronological age was equivalent to the number of seasonal cycles experienced by the mouse lemurs. For colony 2, in which seasonal cycles were accelerated by a factor of 1.5, mouse lemurs had experienced 4.13 ± 1.50 seasonal cycles in 2.75 ± 0.99 chronological years. DISCUSSION: Our study showed clear differences in age at the onset of nuclear sclerosis formation between lemurs kept under different photoperiodic regimes. Instead of measuring the chronological age, the number of seasonal cycles (N = four) experienced by a mouse lemur can be used to estimate the risk of beginning nuclear sclerosis formation. Ophthalmological examinations should be taken into account when animals older than 5-6 seasonal cycles are used for experiments in which unrestricted visual ability has to be ensured. This study is the first to assess and demonstrate the influence of annual photoperiod regime on the incidence of lens opacities in a non-human primate.

Nanoparticles as contrast agents for brain nuclear magnetic resonance imaging in Alzheimer's disease diagnosis.

Nuclear Magnetic Resonance Imaging (MRI) of amyloid plaques is a powerful non-invasive approach for the early and accurate diagnosis of Alzheimer's disease (AD) along with clinical observations of behavioral changes and cognitive impairment. The present article aims at giving a critical and comprehensive review of recent advances in the development of nanoparticle-based contrast agents for brain MRI. Nanoparticles considered for the MRI of AD must comply with a highly stringent set of requirements including low toxicity and the ability to cross the blood-brain-barrier. In addition, to reach an optimal signal-to-noise ratio, they must exhibit a specific ability to target amyloid plaques, which can be achieved by grafting antibodies, peptides or small molecules. Finally, we propose to consider new directions for the future of MRI in the context of Alzheimer's disease, in particular by enhancing the performances of contrast agents and by including therapeutic functionalities following a theranostic strategy.

A Fluorescent Oligothiophene-Bis-Triazine ligand interacts with PrP fibrils and detects SDS-resistant oligomers in human prion diseases.

BACKGROUND: Prion diseases are characterized by the accumulation in the central nervous system of an abnormally folded isoform of the prion protein, named PrP(Sc). Aggregation of PrP(Sc) into oligomers and fibrils is critically involved in the pathogenesis of prion diseases. Oligomers are supposed to be the key neurotoxic agents in prion disease, so modulation of prion aggregation pathways with small molecules can be a valuable strategy for studying prion pathogenicity and for developing new diagnostic and therapeutic approaches. We previously identified thienyl pyrimidine compounds that induce SDS-resistant PrP(Sc) (rSDS-PrP(Sc)) oligomers in prion-infected samples. RESULTS: Due to the low effective doses of the thienyl pyrimidine hits, we synthesized a quaterthiophene-bis-triazine compound, called MR100 to better evaluate their diagnostic and therapeutic potentials. This molecule exhibits a powerful activity inducing rSDS-PrP(Sc) oligomers at nanomolar concentrations in prion-infected cells. Fluorescence interaction studies of MR100 with mouse PrP fibrils showed substantial modification of the spectrum, and the interaction was confirmed in vitro by production of rSDS-oligomer species upon incubation of MR100 with fibrils in SDS-PAGE gel. We further explored whether MR100 compound has a potential to be used in the diagnosis of prion diseases. Our results showed that: (i) MR100 can detect rSDS-oligomers in prion-infected brain homogenates of various species, including human samples from CJD patients; (ii) A protocol, called "Rapid Centrifugation Assay" (RCA), was developed based on MR100 property of inducing rSDS-PrP(Sc) oligomers only in prion-infected samples, and avoiding the protease digestion step. RCA allows the detection of both PK-sensitive and PK-resistant PrP(Sc) species in rodents samples but also from patients with different CJD forms (sporadic and new variant); (iii) A correlation could be established between the amount of rSDS-PrP(Sc) oligomers revealed by MR100 and the duration of the symptomatic phase of the disease in CJD patients; and (iv) Bioassay experiments showed that MR100 can trap prion infectivity more efficiently than P30 drug. CONCLUSIONS: MR100 is a powerful tool not only for studying the prion aggregation pathways regarding oligomeric and sPrP(Sc) species, but also for developing alternative methods for the detection of prion-infected samples. Considering our bioassay results, MR100 is a promising molecule for the development of prion decontamination approaches.

Lessons from the analysis of nonhuman primates for understanding human aging and neurodegenerative diseases.

Animal models are necessary tools for solving the most serious challenges facing medical research. In aging and neurodegenerative disease studies, rodents occupy a place of choice. However, the most challenging questions about longevity, the complexity and functioning of brain networks or social intelligence can almost only be investigated in nonhuman primates. Beside the fact that their brain structure is much closer to that of humans, they develop highly complex cognitive strategies and they are visually-oriented like humans. For these reasons, they deserve consideration, although their management and care are more complicated and the related costs much higher. Despite these caveats, considerable scientific advances have been possible using nonhuman primates. This review concisely summarizes their role in the study of aging and of the mechanisms involved in neurodegenerative disorders associated mainly with cognitive dysfunctions (Alzheimer's and prion diseases) or motor deficits (Parkinson's and related diseases).

CXCR7 Receptor Controls the Maintenance of Subpial Positioning of Cajal-Retzius Cells.

Cajal-Retzius (CR) cells are essential for cortical development and lamination. These pioneer neurons arise from distinct progenitor sources, including the cortical hem and the ventral pallium at pallium-subpallium boundary (PSB). CXCR4, the canonical receptor for the chemokine CXCL12, controls the superficial location of hem-derived CR cells. However, recent studies showed that CXCR7, a second CXCL12 receptor, is also expressed in CR cells at early developmental stages. We thus investigated the role of CXCR7 during CR cell development using multiple loss-of-function approaches. Cxcr7 gene inactivation led to aberrant localization of Reelin-positive cells within the pallium. In addition, Cxcr7(-/-) mice were characterized by significant accumulation of ectopic CR cells in the lateral part of the dorsal pallium compared with Cxcr4 knockout mice. Loss-of-function approaches, using either gene targeting or pharmacological receptor inhibition, reveal that CXCR7 and CXCR4 act both in CR positioning. Finally, conditional Cxcr7 deletion in cells derived from Dbx1-expressing progenitors indicates an essential role of CXCR7 in controlling the positioning of a subpopulation of PSB-derived CR cells. Our data demonstrate that CXCR7 has a role in the positioning of hem and PSB-derived CR cells, CXCL12 regulating CR cell subpial localization through the combined action of CXCR4 and CXCR7.

Corrective GUSB transfer to the canine mucopolysaccharidosis VII cornea using a helper-dependent canine adenovirus vector.

Corneal transparency is maintained, in part, by specialized fibroblasts called keratocytes, which reside in the fibrous lamellae of the stroma. Corneal clouding, a condition that impairs visual acuity, is associated with numerous diseases, including mucopolysaccharidosis (MPS) type VII. MPS VII is due to deficiency in ß-glucuronidase (ß-glu) enzymatic activity, which leads to accumulation of glycosaminoglycans (GAGs), and secondary accumulation of gangliosides. Here, we tested the efficacy of canine adenovirus type 2 (CAV-2) vectors to transduce keratocyte in vivo in mice and nonhuman primates, and ex vivo in dog and human corneal explants. Following efficacy studies, we asked if we could treat corneal clouding by the injection a helper-dependent (HD) CAV-2 vector (HD-RIGIE) harboring the human cDNA coding for ß-glu (GUSB) in the canine MPS VII cornea. ß-Glu activity, GAG content, and lysosome morphology and physiopathology were analyzed. We found that HD-RIGIE injections efficiently transduced coxsackievirus adenovirus receptor-expressing keratocytes in the four species and, compared to mock-injected controls, improved the pathology in the canine MPS VII cornea. The key criterion to corrective therapy was the steady controlled release of ß-glu and its diffusion throughout the collagen-dense stroma. These data support the continued evaluation of HD CAV-2 vectors to treat diseases affecting corneal keratocytes.

Thienyl pyrimidine derivatives with PrP(Sc) oligomer-inducing activity are a promising tool to study prions.

Transmissible spongiform encephalopathies (TSEs), also called prion diseases, are fatal, infectious, genetic or sporadic neurodegenerative disorders of humans and animals. In humans, TSEs are represented by Creutzfeldt-Jakob disease (CJD), Gerstmann-Sträussler-Scheinker syndrome, Fatal Familial Insomnia and Kuru. In animals, the most prominent prion diseases are scrapie of sheep and goats, bovine spongiform encephalopathy (BSE) of cattle and chronic wasting disease (CWD) of deer and elk. A critical event in prion diseases is the accumulation in the central nervous system (CNS) of the abnormally folded PrP(Sc) protein that is the protease-resistant isoform of a normal cellular protein encoded by the host and called PrP(C). PrP(Sc) (also known as rPrP(Sc) or PrP27-30) represents the main marker of prion diseases and is routinely used in the reference method for the diagnosis of prion diseases. Most of the therapeutic strategies developed so far aimed at identifying compounds that diminish the levels of PrP(Sc), with variable success when tested in vivo. In this review, we present an alternative approach in which small molecules that induce PrP(Sc) oligomers are identified. By using virtual and cellular screenings, we found several thienyl pyrimidine compounds that trigger PrP(Sc) oligomerization and trap prion infectivity.

Amyloid beta immunization worsens iron deposits in the choroid plexus and cerebral microbleeds.

Anti-amyloid beta (Aß) immunotherapy provides potential benefits in Alzheimer's disease patients. Nevertheless, strategies based on Aß1-42 peptide induced encephalomyelitis and possible microhemorrhages. These outcomes were not expected from studies performed in rodents. It is critical to determine if other animal models better predict side effects of immunotherapies. Mouse lemur primates can develop amyloidosis with aging. Here we used old lemurs to study immunotherapy based on Aß1-42 or Aß-derivative (K6Aß1-30). We followed anti-Aß40 immunoglobulin G and M responses and Aß levels in plasma. In vivo magnetic resonance imaging and histology were used to evaluate amyloidosis, neuroinflammation, vasogenic edema, microhemorrhages, and brain iron deposits. The animals responded mainly to the Aß1-42 immunogen. This treatment induced immune response and increased Aß levels in plasma and also microhemorrhages and iron deposits in the choroid plexus. A complementary study of untreated lemurs showed iron accumulation in the choroid plexus with normal aging. Worsening of iron accumulation is thus a potential side effect of Aß-immunization at prodromal stages of Alzheimer's disease, and should be monitored in clinical trials.

Increased amyloid-ß peptide-induced memory deficits in phospholipid transfer protein (PLTP) gene knockout mice.

Oxidative stress is recognized as one of the earliest and most intense pathological processes in Alzheimer's disease (AD), and the antioxidant vitamin E has been shown to efficiently prevent amyloid plaque formation and neurodegeneration. Plasma phospholipid transfer protein (PLTP) has a major role in vitamin E transfers in vivo, and PLTP deficiency in mice is associated with reduced brain vitamin E levels. To determine the impact of PLTP on amyloid pathology in vivo, we analyzed the vulnerability of PLTP-deficient (PLTP-KO) mice to the toxic effects induced by intracerebroventricular injection of oligomeric amyloid-ß 25-35 (Aß 25-35) peptide, a non-transgenic model of AD. Under basal conditions, PLTP-KO mice showed increased cerebral oxidative stress, increased brain Aß 1-42 levels, and a lower expression of the synaptic function marker synaptophysin, as compared with wild-type mice. This PLTP-KO phenotype was associated with increased memory impairment 1 week after Aß25-35 peptide injection. Restoration of brain vitamin E levels in PLTP-KO mice through a chronic dietary supplementation prevented Aß 25-35-induced memory deficits and reduced cerebral oxidative stress and toxicity. We conclude that PLTP, through its ability to deliver vitamin E to the brain, constitutes an endogenous neuroprotective agent. Increasing PLTP activity may offer a new way to develop neuroprotective therapies.

[The diversity of aging models]. / Aperçu de la diversité des modèles animaux dédiés à l'étude du vieillissement.

Most of the signalling pathways involved in aging regulation have been recently found well conserved at various levels throughout the evolution. Taking this into account, a diversity of model organisms, including worms, rodents, and lemurs as well, allows to address different questions: how to understand the interactions between genetic and environmental factors while challenging theories of aging, to preserve hearing integrity, to fight against senescence of neural stem cells, or to explore brain fitness from gene expression to cognitive and social behavior? Here are the main issues that can be considered, stressing the complementarities of the models. The differentiation of aging physiological aspects from those induced by age-related pathologies will also be specified. By emphasizing recent ability of technologies to promote new aging insights, we discuss towards a better understanding of mechanisms governing aging.