No model fully recapitulates the neuropathology of Alzheimer's disease (AD). Although the triple‐transgenic mouse model of AD (3xTg‐AD) expresses Aβ plaques and tau‐laden neurofibrillary tangles, as ...well as synaptic and behavioral deficits, it does not display frank neuronal loss. Because old age is the most important risk factor in AD, senescence‐related interactions might be lacking to truly establish an AD‐like environment. To investigate this hypothesis, we bred the 3xTg‐AD mouse with the senescence‐accelerated mouse prone 8 (SAMP8), a model of accelerated aging. We generated four groups of heterozygous mice with either the SAMP8 or SAMR1 (senescence‐resistant‐1) genotype, along with either the 3xTg‐AD or non‐transgenic (NonTg) genotype. Despite no differences among groups in total latency to escape the Barnes maze, a greater number of errors were noticed before entering the target hole in 19‐month‐old P8/3xTg‐AD mice at day 5, compared to other groups. Postmortem analyses revealed increased cortical levels of phospho‐tau (Thr231) in female P8/3xTg‐AD mice (+277% vs. R1/3xTg‐AD mice), without other tau‐related changes. Female P8/3xTg‐AD mice exhibited higher cortical soluble Aβ40 and Aβ42 concentrations (Aβ40, +85%; Aβ42, +35% vs. R1/3xTg‐AD), whereas insoluble forms remained unchanged. Higher Aβ42 load coincided with increased astroglial activation in female P8/3xTg‐AD mice, as measured with glial fibrillary acidic protein (GFAP) (+57% vs. R1/3xTg‐AD mice). To probe neuronal degeneration, concentrations of neuronal nuclei (NeuN) were measured, but no differences were detected between groups. Altogether, the SAMP8 genotype had deleterious effects on spatial memory and exerted female‐specific aggravation of AD neuropathology without overt neurodegeneration in 3xTg‐AD mice.
Heterozygous female 3xTg‐AD mice with senescence‐accelerated prone 8 (SAMP8) background displayed a more severe AD‐like neuropathology compared to senescence‐resistant‐1 (SAMR1) controls.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Combined evidence from neuroimaging and neuropathological studies shows that signs of vascular pathology and brain hypoperfusion develop early in Alzheimer's disease (AD). To investigate the ...functional implication of these abnormalities, we have studied the cerebrovascular volume and selected markers of blood–brain barrier (BBB) integrity in 11-month-old 3×Tg-AD mice, using the in situ brain perfusion technique. The cerebrovascular volume of distribution of two vascular space markers, 3H-inulin and 14C-sucrose, was significantly lower (−26% and −27%, respectively; p<0.01) in the brain of 3×Tg-AD mice compared to non-transgenic littermates. The vascular volume reduction was significant in the hippocampus (p<0.01), but not in the frontal cortex and cerebellum. However, the brain transport coefficient (Clup) of 14C-d-glucose (1μM) and 3H-diazepam was similar between 3×Tg-AD mice and controls, suggesting no difference in the functional integrity of the BBB. We also report a 32% increase (p<0.001) in the thickness of basement membranes surrounding cortical microvessels along with a 20% increase (p<0.05) of brain collagen content in 3×Tg-AD mice compared to controls. The present data indicate that the cerebrovascular space is reduced in a mouse model of Aβ and tau accumulation, an observation consistent with the presence of cerebrovascular pathology in AD.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, SAZU, SBCE, UL, UM, UPCLJ, UPUK
Abstract In simple systems, lifespan can be extended by various methods including dietary restriction, mutations in the insulin/insulin-like growth factor (IGF) pathway or mitochondria among other ...processes. It is widely held that the mechanisms that extend lifespan may be adapted for diminishing age-associated pathologies. We tested whether a number of compounds reported to extend lifespan in C. elegans could reduce age-dependent toxicity caused by mutant TAR DNA-binding protein-43 in C. elegans motor neurons. Only half of the compounds tested show protective properties against neurodegeneration, suggesting that extended lifespan is not a strong predictor for neuroprotective properties. We report here that resveratrol, rolipram, reserpine, trolox, propyl gallate, and ethosuximide protect against mutant TAR DNA-binding protein-43 neuronal toxicity. Finally, of all the compounds tested, only resveratrol required daf-16 and sir-2.1 for protection, and ethosuximide showed dependence on daf-16 for its activity.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
n-3 PUFA are receiving growing attention for their therapeutic potential in central nervous system (CNS) disorders. We have recently shown that long-term treatment with DHA alters the physiology of ...entorhinal cortex (EC) neurons. In the present study, we investigated by patch-clamp the effect of another major dietary n-3 PUFA, α-linolenic acid (LNA), on the intrinsic properties of EC neurons. Mice were chronically exposed to isoenergetic diets deficient in n-3 PUFA or enriched in either DHA or LNA on an equimolar basis. GC analyses revealed an increase in DHA (34 %) and a decrease in arachidonic acid (AA, − 23 %) in brain fatty acid concentrations after consumption of the DHA-enriched diet. Dietary intake of LNA similarly affected brain fatty acid profiles, but at a lower magnitude (DHA: 23 %, AA: − 13 %). Compared to the n-3 PUFA-deficient diet, consumption of DHA, but not LNA, induced membrane hyperpolarisation ( − 60 to − 70 mV), increased cellular capacitance (32 %) and spontaneous excitatory postsynaptic current frequency (50 %). We propose that the inefficiency of LNA to modulate cellular capacitance was related to its inability to increase the brain DHA:AA ratio over the threshold necessary to up-regulate syntaxin-3 (46 %) and translocate drebrin (40 % membrane:cytosol ratio). In summary, our present study shows that the increase in brain DHA content following chronic administration of LNA was not sufficient to alter the passive and synaptic properties of EC neurons, compared to direct dietary intake of DHA. These diverging results have important implications for the therapeutic use of n-3 PUFA in CNS disease, favouring the use of preformed DHA.
n-3 PUFA are receiving growing attention for their therapeutic potential in central nervous system (CNS) disorders. We have recently shown that long-term treatment with DHA alters the physiology of ...entorhinal cortex (EC) neurons. In the present study, we investigated by patch-clamp the effect of another major dietary n-3 PUFA, alpha-linolenic acid (LNA), on the intrinsic properties of EC neurons. Mice were chronically exposed to isoenergetic diets deficient in n-3 PUFA or enriched in either DHA or LNA on an equimolar basis. GC analyses revealed an increase in DHA (34 %) and a decrease in arachidonic acid (AA, - 23 %) in brain fatty acid concentrations after consumption of the DHA-enriched diet. Dietary intake of LNA similarly affected brain fatty acid profiles, but at a lower magnitude (DHA: 23 %, AA: - 13 %). Compared to the n-3 PUFA-deficient diet, consumption of DHA, but not LNA, induced membrane hyperpolarisation ( - 60 to - 70 mV), increased cellular capacitance (32 %) and spontaneous excitatory postsynaptic current frequency (50 %). We propose that the inefficiency of LNA to modulate cellular capacitance was related to its inability to increase the brain DHA:AA ratio over the threshold necessary to up-regulate syntaxin-3 (46 %) and translocate drebrin (40 % membrane:cytosol ratio). In summary, our present study shows that the increase in brain DHA content following chronic administration of LNA was not sufficient to alter the passive and synaptic properties of EC neurons, compared to direct dietary intake of DHA. These diverging results have important implications for the therapeutic use of n-3 PUFA in CNS disease, favouring the use of preformed DHA. PUBLICATION ABSTRACT
Hereditary spastic paraplegias (HSPs) are a group of neurodegenerative diseases causing progressive gait dysfunction. Over 50 genes have now been associated with HSP. Despite the recent explosion in ...genetic knowledge, HSP remains without pharmacological treatment. Loss-of-function mutation of the SPAST gene, also known as SPG4, is the most common cause of HSP in patients. SPAST is conserved across animal species and regulates microtubule dynamics. Recent studies have shown that it also modulates endoplasmic reticulum (ER) stress. Here, utilizing null SPAST homologues in C. elegans, Drosophila and zebrafish, we tested FDA-approved compounds known to modulate ER stress in order to ameliorate locomotor phenotypes associated with HSP. We found that locomotor defects found in all of our spastin models could be partially rescued by phenazine, methylene blue, N-acetyl-cysteine, guanabenz and salubrinal. In addition, we show that established biomarkers of ER stress levels correlated with improved locomotor activity upon treatment across model organisms. Our results provide insights into biomarkers and novel therapeutic avenues for HSP.
The histopathological hallmarks of Alzheimer disease (AD) include intraneuronal neurofibrillary tangles composed of abnormally hyperphosphorylated τ protein. Insulin dysfunction might influence AD ...pathology, as population-based and cohort studies have detected higher AD incidence rates in diabetic patients. But how diabetes affects τ pathology is not fully understood. In this study, we investigated the impact of insulin dysfunction on τ phosphorylation in a genetic model of spontaneous type 1 diabetes: the nonobese diabetic (NOD) mouse. Brains of young and adult female NOD mice were examined, but young NOD mice did not display τ hyperphosphorylation. τ phosphorylation at τ-1 and pS422 epitopes was slightly increased in nondiabetic adult NOD mice. At the onset of diabetes, τ was hyperphosphorylated at the τ-1, AT8, CP13, pS262, and pS422. A subpopulation of diabetic NOD mice became hypothermic, and τ hyperphosphorylation further extended to paired helical filament-1 and TG3 epitopes. Furthermore, elevated τ phosphorylation correlated with an inhibition of protein phosphatase 2A (PP2A) activity. Our data indicate that insulin dysfunction in NOD mice leads to AD-like τ hyperphosphorylation in the brain, with molecular mechanisms likely involving a deregulation of PP2A. This model may be a useful tool to address further mechanistic association between insulin dysfunction and AD pathology.
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 < 0.001), including docosahexaenoic acid (DHA; +5%, p < 0.001) in 20 month-old mice. The expression of fat-1 decreased the levels of soluble Aβ₄₂ (-41%, p < 0.01) at 20 months without reducing the level of insoluble forms of Aβ₄₀ and Aβ₄₂ in the brain of 3 × Tg-AD mice. The 3 × Tg-AD/Fat-1 mice exhibited lower cortical levels of both soluble (-25%, p < 0.05) and insoluble phosphorylated tau (-55%, p < 0.05) compared to 3 × Tg-AD mice, but only in 20 month-old animals. Whereas a decrease of calcium/calmodulin-dependent protein kinase II was observed in 3 × Tg-AD/Fat-1 mice (-039%, p < 0.05), altered tau phosphorylation could not be related to changes in glycogen synthase kinase 3β, cyclin-dependent kinase 5, or protein phosphatase type 2A enzymatic activity. In addition, the expression of the fat-1 transgene prevented the increase of glial fibrillary acidic protein (-37%, p < 0.01) observed in 20 month-old 3 × Tg-AD mice. In conclusion, the expression of fat-1 in 3 × Tg-AD mice increases brain DHA and induces biomarker changes that are consistent with a beneficial effect against an AD-like neuropathology.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
J. Neurochem. (2012) 122, 427–443.
Dietary lipids modify brain fatty acid profile, but evidence of their direct effect on neuronal function is sparse. The enthorinal cortex (EC) neurons connecting to ...the hippocampus play a critical role in learning and memory. Here, we have exposed mice to diets based on canola:soybean oils (40 : 10, g/kg) or safflower : corn oils (25 : 25, g/kg) to investigate the relationship between the lipid profile of brain fatty acids and the intrinsic properties of EC neurons. Consumption of canola : soybean oil‐enriched diet led to the increase of the monounsaturated fatty acid oleic acid and to a decrease of arachidonic acid in ethanolamine glycerophospholipids of the white matter. We also found an important rise in docosahexaenoic acid (DHA) within ethanolamine glycerophospholipids and phosphatidylserine of gray matter. The canola:soybean oil treatment led to a shorter duration of action potential (−21%), a reduction in the duration of postsynaptic response (−21%) and increased firing activity (+43%). Data from additional experiments with animals fed DHA alone or DHA with canola oil suggested that dietary monounsaturated fatty acid may have contributed to these effects on EC neuron physiology. Since neuronal function within the enthorhinal‐hippocampal loop is critical to learning and memory processes, the present data may provide a functional basis for the beneficial cognitive effects of canola oil‐based diets.
High‐MUFA intake increased oleic acid (OLA) and decreased arachidonic acid (ARA) in phospholipids of myelinated axons in the brain white matter. Such diet‐induced changes were associated with narrower action potentials and shorter postsynaptic responses in pyramidal neurons from the entorhinal cortex, which could have profound impact on brain function.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Exposure to the beta-amyloid peptide (Abeta) is toxic to neurons and other cell types, but the mechanism(s) involved are still unresolved. Synthetic Abeta oligomers can induce ion-permeable pores in ...synthetic membranes, but whether this ability to damage membranes plays a role in the ability of Abeta oligomers to induce tau hyperphosphorylation, or other disease-relevant pathological changes, is unclear. To examine the cellular responses to Abeta exposure independent of possible receptor interactions, we have developed an in vivo C. elegans model that allows us to visualize these cellular responses in living animals. We find that feeding C. elegans E. coli expressing human Abeta induces a membrane repair response similar to that induced by exposure to the CRY5B, a known pore-forming toxin produced by B. thuringensis. This repair response does not occur when C. elegans is exposed to an Abeta Gly37Leu variant, which we have previously shown to be incapable of inducing tau phosphorylation in hippocampal neurons. The repair response is also blocked by loss of calpain function, and is altered by loss-of-function mutations in the C. elegans orthologs of BIN1 and PICALM, well-established risk genes for late onset Alzheimer's disease. To investigate the role of membrane repair on tau phosphorylation directly, we exposed hippocampal neurons to streptolysin O (SLO), a pore-forming toxin that induces a well-characterized membrane repair response. We find that SLO induces tau hyperphosphorylation, which is blocked by calpain inhibition. Finally, we use a novel biarsenical dye-tagging approach to show that the Gly37Leu substitution interferes with Abeta multimerization and thus the formation of potentially pore-forming oligomers. We propose that Abeta-induced tau hyperphosphorylation may be a downstream consequence of induction of a membrane repair process. Keywords: Alzheimer's disease, beta-amyloid, Tau, Caenorhabditis elegans, Pore-forming toxin
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