Differential impact of eicosapentaenoic acid and docosahexaenoic acid in an animal model of Alzheimer's disease.

Dietary supplementation with n-3 polyunsaturated fatty acids improves cognitive performance in several animal models of Alzheimer's disease (AD), an effect often associated with reduced amyloid-beta and/or tau pathologies. However, it remains unclear to what extent eicosapentaenoic (EPA) provides additional benefits compared to docosahexaenoic acid (DHA). Here, male and female 3xTg-AD mice were fed for 3 months (13-16 months of age) the following diets: (1) control (no DHA/EPA), (2) DHA (1.

Additive neurorestorative effects of exercise and docosahexaenoic acid intake in a mouse model of Parkinson's disease.

JOURNAL/nrgr/04.03/01300535-202502000-00033/figure1/v/2024-05-28T214302Z/r/image-tiff There is a need to develop interventions to slow or reverse the degeneration of dopamine neurons in Parkinson's disease after diagnosis. Given that preclinical and clinical studies suggest benefits of dietary n-3 polyunsaturated fatty acids, such as docosahexaenoic acid, and exercise in Parkinson's disease, we investigated whether both could synergistically interact to induce recovery of the dopaminergic pathway.

Postsynaptic Protein Shank3a Deficiency Synergizes with Alzheimer's Disease Neuropathology to Impair Cognitive Performance in the 3xTg-AD Murine Model.

Synaptic loss is intrinsically linked to Alzheimer's disease (AD) neuropathology and symptoms, but its direct impact on clinical symptoms remains elusive. The postsynaptic protein Shank3 (SH3 and multiple ankyrin repeat domains) is of particular interest, as the loss of a single allele of the gene is sufficient to cause profound cognitive symptoms in children. We thus sought to determine whether a SHANK3 deficiency could contribute to the emergence or worsening of AD symptoms and neuropathology.

Higher Angiotensin I Converting Enzyme 2 (ACE2) levels in the brain of individuals with Alzheimer's disease.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a major cause of death in the elderly. Cognitive decline due to Alzheimer's disease (AD) is frequent in the geriatric population disproportionately affected by the COVID-19 pandemic. Interestingly, central nervous system (CNS) manifestations have been reported in SARS-CoV-2-infected patients.

Cerebrovascular insulin receptors are defective in Alzheimer's disease.

Central response to insulin is suspected to be defective in Alzheimer's disease. As most insulin is secreted in the bloodstream by the pancreas, its capacity to regulate brain functions must, at least partly, be mediated through the cerebral vasculature. However, how insulin interacts with the blood-brain barrier and whether alterations of this interaction could contribute to Alzheimer's disease pathophysiology both remain poorly defined.

Combining NGN2 programming and dopaminergic patterning for a rapid and efficient generation of hiPSC-derived midbrain neurons.

The use of human derived induced pluripotent stem cells (hiPSCs) differentiated to dopaminergic (DA) neurons offers a valuable experimental model to decorticate the cellular and molecular mechanisms of Parkinson's disease (PD) pathogenesis. However, the existing approaches present with several limitations, notably the lengthy time course of the protocols and the high variability in the yield of DA neurons. Here we report on the development of an improved approach that combines neurogenin-2 programming with the use of commercially available midbrain differentiation kits for a rapid, efficient, and reproducible directed differentiation of hiPSCs to mature and functional induced DA (iDA) neurons, with minimum contamination by other brain cell types.

Sex-dependent alterations in the physiology of entorhinal cortex neurons in old heterozygous 3xTg-AD mice.

While the higher prevalence of Alzheimer's disease (AD) in women is clear, studies suggest that biological sex may also influence AD pathogenesis. However, mechanisms behind these differences are not clear. To investigate physiological differences between sexes at the cellular level in the brain, we investigated the intrinsic and synaptic properties of entorhinal cortex neurons in heterozygous 3xTg-AD mice of both sexes at the age of 20 months.

Dietary intake of branched-chain amino acids in a mouse model of Alzheimer's disease: Effects on survival, behavior, and neuropathology.

Introduction: High levels of plasmatic branched-chain amino acids (BCAA), commonly used as dietary supplements, are linked to metabolic risk factors for Alzheimer's disease (AD). BCAA directly influence amino acid transport to the brain and, therefore, neurotransmitter levels. We thus investigated the impact of BCAA on AD neuropathology in a mouse model.

Impact of DHA intake in a mouse model of synucleinopathy.

Polyunsaturated fatty acids omega-3 (n-3 PUFA), such as docosahexaenoic acid (DHA), have been shown to prevent, and partially reverse, neurotoxin-induced nigrostriatal denervation in animal models of Parkinson's disease (PD). However, the accumulation of α-synuclein (αSyn) in cerebral tissues is equally important to the pathophysiology. To determine whether DHA intake improves various aspects related to synucleinopathy, ninety male mice overexpressing human αSyn under the Thy-1 promoter (Thy1-αSyn) were fed one of three diets (specially formulated control, low n-3 PUFA or high DHA) and compared to non-transgenic C57/BL6 littermate mice exposed to a control diet.

Internalization of targeted quantum dots by brain capillary endothelial cells in vivo.

Receptors located on brain capillary endothelial cells forming the blood-brain barrier are the target of most brain drug delivery approaches. Yet, direct subcellular evidence of vectorized transport of nanoformulations into the brain is lacking. To resolve this question, quantum dots were conjugated to monoclonal antibodies (Ri7) targeting the murine transferrin receptor.

Spontaneous reaction between an uncharged lithium iron silicate cathode and a LiPF6-based electrolyte.

The reaction between an uncharged Li2FeSiO4 (LFS) cathode and a LiPF6-EC/DMC electrolyte is revealed by in situ XANES in coin cells. This study shows clear evidence of delithiation and iron oxidation in LFS prior to cycling. Subsequent cycling appears to partially restore the original lithiation level, an observation that needs to be taken into consideration in future LFS development work.

Insulin reverses the high-fat diet-induced increase in brain Aβ and improves memory in an animal model of Alzheimer disease.

Defects in insulin production and signaling are suspected to share a key role in diabetes and Alzheimer disease (AD), two age-related pathologies. In this study, we investigated the interrelation between AD and diabetes using a high-fat diet (HFD) in a mouse model of genetically induced AD-like neuropathology (3xTg-AD). We first observed that cerebral expression of human AD transgenes led to peripheral glucose intolerance, associated with pancreatic human Aβ accumulation.

Increased LINGO1 in the cerebellum of essential tremor patients.

Essential tremor (ET) is the most prevalent adult-onset movement disorder. Despite its health burden, no clear pathognomonic sign has been identified to date because of the rarity of clinicopathological studies. Moreover, treatment options are still scarce and have not significantly changed in the last 30 years, underscoring the urgent need to develop new treatment avenues.

Brain uptake of a fluorescent vector targeting the transferrin receptor: a novel application of in situ brain perfusion.

Monoclonal antibodies (mAbs) targeting blood-brain barrier (BBB) transporters are being developed for brain drug targeting. However, brain uptake quantification remains a challenge, particularly for large compounds, and often requires the use of radioactivity. In this work, we adapted an in situ brain perfusion technique for a fluorescent mAb raised against the mouse transferrin receptor (TfR) (clone Ri7).

Defective dentate nucleus GABA receptors in essential tremor.

The development of new treatments for essential tremor, the most frequent movement disorder, is limited by a poor understanding of its pathophysiology and the relative paucity of clinicopathological studies. Here, we report a post-mortem decrease in GABA(A) (35% reduction) and GABA(B) (22-31% reduction) receptors in the dentate nucleus of the cerebellum from individuals with essential tremor, compared with controls or individuals with Parkinson's disease, as assessed by receptor-binding autoradiography. Concentrations of GABA(B) receptors in the dentate nucleus were inversely correlated with the duration of essential tremor symptoms (r(2) = 0.

Endogenous conversion of omega-6 into omega-3 fatty acids improves neuropathology in an animal model of Alzheimer's disease.

Dietary supplementation with n-3 polyunsaturated fatty acids (n-3 PUFA) reduces amyloid-β (Aβ) and tau pathology and improves cognitive performance in animal models of Alzheimer's disease (AD). To exclude confounding variables associated with the diet, we crossed 3 × Tg-AD mice (modeling AD neuropathology) with transgenic Fat-1 mice that express the fat-1 gene encoding a PUFA desaturase, which endogenously produces n-3 PUFA from n-6 PUFA. The expression of fat-1 shifted the n-3:n-6 PUFA ratio upward in the brain (+11%, p < 0.

In vivo labeling of brain capillary endothelial cells after intravenous injection of monoclonal antibodies targeting the transferrin receptor.

The development of vectors for drug delivery to the central nervous system remains a major pharmaceutical challenge. Here, we have characterized the brain distribution of two monoclonal antibodies (MAbs) targeting the mouse transferrin receptor (TfR) (clones Ri7 and 8D3) compared with control IgGs after intravenous injection into mice. MAbs were fluorolabeled with either Alexa Fluor (AF) dyes 647 or 750.

Neuroinflammation is associated with changes in glial mGluR5 expression and the development of neonatal excitotoxic lesions.

It has been hypothesized that neuroinflammation triggered during brain development can alter brain functions later in life. We investigated the contribution of inflammation to the alteration of normal brain circuitries in the context of neuroexcitotoxicity following neonatal ventral hippocampal lesions in rats with ibotenic acid, an NMDA glutamate receptor agonist. Excitotoxic ibotenic acid lesions led to a significant and persistent astrogliosis and microglial activation, associated with the production of inflammatory mediators.

Transgenic conversion of omega-6 into omega-3 fatty acids in a mouse model of Parkinson's disease.

We have recently identified a neuroprotective role for omega-3 polyunsaturated fatty acids (n-3 PUFAs) in a toxin-induced mouse model of Parkinson's disease (PD). Combined with epidemiological data, these observations suggest that low n-3 PUFA intake is a modifiable environmental risk factor for PD. In order to strengthen these preclinical findings as prerequisite to clinical trials, we further investigated the neuroprotective role of n-3 PUFAs in Fat-1 mice, a transgenic model expressing an n-3 fatty acid desaturase converting n-6 PUFAs into n-3 PUFAs.

Diffusion of docosahexaenoic and eicosapentaenoic acids through the blood-brain barrier: An in situ cerebral perfusion study.

Docosahexaenoic (DHA) and eicosapentaenoic (EPA) acids are n-3 polyunsaturated fatty acids with a therapeutic potential for CNS diseases. Here, using an in situ brain perfusion technique in mice, we show that [(14)C]-DHA and [(14)C]-EPA readily cross the mouse blood-brain barrier (BBB) with brain transport coefficients (Clup) of 48+/-3microlg(-1)s(-1) and 52+/-4microlg(-1)s(-1), respectively. Mechanical capillary depletion of brain homogenates showed that less than 10% of [(14)C]-DHA or [(14)C]-EPA remained in endothelial cells of the brain vasculature, demonstrating that both molecules fully crossed the BBB.

Sirtuin 1 reduction parallels the accumulation of tau in Alzheimer disease.

Aging and metabolism-related disorders are risk factors for Alzheimer disease (AD). Because sirtuins may increase the life span through regulation of cellular metabolism, we compared the concentration of sirtuin 1 (SIRT1) in the brains of AD patients (n = 19) and controls (n = 22) using Western immunoblots and in situ hybridization. We report a significant reduction of SIRT1 (messenger RNA [mRNA], -29%; protein, -45%) in the parietal cortex of AD patients, but not in the cerebellum.

High-fat diet aggravates amyloid-beta and tau pathologies in the 3xTg-AD mouse model.

To investigate potential dietary risk factors of Alzheimer's disease (AD), triple transgenic (3xTg-AD) mice were exposed from 4 to 13 months of age to diets with a low n-3:n-6 polyunsaturated fatty acid (PUFA) ratio incorporated in either low-fat (5% w/w) or high-fat (35% w/w) formulas and compared with a control diet. The n-3:n-6 PUFA ratio was decreased independently of the dietary treatments in the frontal cortex of 3xTg-AD mice compared to non-transgenic littermates. Consumption of a high-fat diet with a low n-3:n-6 PUFA ratio increased amyloid-beta (Abeta) 40 and 42 concentrations in detergent-insoluble extracts of parieto-temporal cortex homogenates from 3xTg-AD mice.