Dietary docosahexaenoic acid (DHA) downregulates liver DHA synthesis by inhibiting eicosapentaenoic acid elongation.

DHA is abundant in brain where it regulates cell survival, neurogenesis and neuroinflammation. DHA can be obtained from the diet or synthesized from alpha-linolenic acid (ALA; 18:3n-3) via a series of desaturation and elongation reactions occurring in the liver. Tracer studies suggest that dietary DHA can downregulate its own synthesis, but the mechanism remains undetermined and is the primary objective of this paper. First, we show by tracing 13C content (δ13C) of DHA via compound-specific isotope analysis (CSIA), that following low dietary DHA, the brain receives DHA synthesized from ALA. We then show that dietary DHA increases mouse liver and serum EPA, which is dependant on ALA. Furthermore, by CSIA we demonstrate that the source of increased EPA is slowed EPA metabolism, not increased DHA retroconversion as previously assumed. DHA feeding alone or with ALA lowered liver elongation of very long-chain (ELOVL2, EPA elongation) enzyme activity despite no change in protein content. To further evaluate the role of ELOVL2, a liver-specific Elovl2 knockout was generated showing that DHA feeding in the presence or absence of a functional liver ELOVL2 yields similar results. An enzyme competition assay for EPA elongation suggests both uncompetitive and non-competitive inhibition by DHA depending on DHA levels. To translate our findings, we show that DHA supplementation in men and women increases EPA levels in a manner dependent on a SNP (rs953413) in the ELOVL2 gene. In conclusion, we identify a novel feedback inhibition pathway where dietary DHA downregulates its liver synthesis by inhibiting EPA elongation.

Neurofilament light-chain (NfL) and 18 kDa translocator protein in early psychosis and its putative high-risk.

Evidence of elevated peripheral Neurofilament light-chain (NfL) as a biomarker of neuronal injury can be utilized to reveal nonspecific axonal damage, which could reflect altered neuroimmune function. To date, only a few studies have investigated NfL as a fluid biomarker in schizophrenia primarily, though none in its putative prodrome (Clinical High-Risk, CHR) or in untreated first-episode psychosis (FEP). Further, it is unknown whether peripheral NfL is associated with 18 kDa translocator protein (TSPO), a validated neuroimmune marker. In this secondary study, we investigated for the first time (1) serum NfL in early stages of psychosis including CHR and FEP as compared to healthy controls, and (2) examined its association with brain TSPO, using [18F]FEPPA positron emission tomography (PET). Further, in the exploratory analyses, we aimed to assess associations between serum NfL and symptom severity in patient group and cognitive impairment in the combined cohort. A large cohort of 84 participants including 27 FEP (24 antipsychotic-naive), 41 CHR (34 antipsychotic-naive) and 16 healthy controls underwent structural brain MRI and [18F]FEPPA PET scan and their blood samples were obtained and assessed for serum NfL concentrations. We found no significant differences in serum NfL levels across clinical groups, controlling for age. We also found no significant association between NfL levels and brain TSPO in the entire cohort. We observed a negative association between serum NfL and negative symptom severity in CHR. Our findings suggest that neither active neuroaxonal deterioration as measured with NfL nor associated neuroimmune activation (TSPO) is clearly identifiable in an early mostly untreated psychosis sample including its putative high-risk.

Upregulated hepatic lipogenesis from dietary sugars in response to low palmitate feeding supplies brain palmitate.

Palmitic acid (PAM) can be provided in the diet or synthesized via de novo lipogenesis (DNL), primarily, from glucose. Preclinical work on the origin of brain PAM during development is scarce and contrasts results in adults. In this work, we use naturally occurring carbon isotope ratios (13C/12C; δ13C) to uncover the origin of brain PAM at postnatal days 0, 10, 21 and 35, and RNA sequencing to identify the pathways involved in maintaining brain PAM, at day 35, in mice fed diets with low, medium, and high PAM from birth. Here we show that DNL from dietary sugars maintains the majority of brain PAM during development and is augmented in mice fed low PAM. Importantly, the upregulation of hepatic DNL genes, in response to low PAM at day 35, demonstrates the presence of a compensatory mechanism to maintain total brain PAM pools compared to the liver; suggesting the importance of brain PAM regulation.

Protein concentrations and activities of fatty acid desaturase and elongase enzymes in liver, brain, testicle, and kidney from mice: Substrate dependency.

The synthesis rates of n-3 and n-6 polyunsaturated fatty acids (PUFAs) in rodents and humans are not agreed upon and depend on substrate availability independently of the capacity for synthesis. Therefore, we aimed to assess the activities of the enzymes for n-3 and n-6 PUFA synthesis pathways in liver, brain, testicle, kidney, heart, and lung, in relation to their protein concentration levels. Eight-week-old Balb/c mice (n = 8) were fed a standard chow diet (6.2% fat, 18.6% protein, and 44.2% carbohydrates) until 14 weeks of age, anesthetized with isoflurane and tissue samples were collected (previously perfused) and stored at -80°C. The protein concentration of the enzymes (Δ-6D, Δ-5D, Elovl2, and Elovl5) were assessed by ELISA kits; their activities were assayed using specific PUFA precursors and measuring the respective PUFA products as fatty acid methyl esters by gas chromatographic analysis. The liver had the highest capacity for PUFA biosynthesis, with limited activity in the brain, testicles, and kidney, while we failed to detect activity in the heart and lung. The protein concentration and activity of the enzymes were significantly correlated. Furthermore, Δ-6D, Δ-5D, and Elovl2 have a higher affinity for n-3 PUFA precursors compared to n-6 PUFA. The capacity for PUFA synthesis in mice mainly resides in the liver, with enzymes having preference for n-3 PUFAs.

Blood and tissue docosahexaenoic acid (DHA, 22:6n-3) turnover rates from Ahiflower® oil are not different than from DHA ethyl ester oil in a diet switch mouse model.

Ahiflower® oil is high in α-linolenic and stearidonic acids, however, tissue/blood docosahexaenoic acid (DHA, 22:6n-3) turnover from dietary Ahiflower oil has not been investigated. In this study, we use compound-specific isotope analysis to determine tissue DHA synthesis/turnover from Ahiflower, flaxseed and DHA oils. Pregnant BALB/c mice (13-17 days) were placed on a 2 % algal DHA oil diet of high carbon-13 content (δ13C) and pups (n = 132) were maintained on the diet until 9 weeks old. Mice were then randomly allocated to a low δ13C-n-3 PUFA diet of either: 1) 4 % Ahiflower oil, 2) 4.35 % flaxseed oil or 3) 1 % fish DHA ethyl ester oil for 1, 3, 7, 14, 30, 60 or 120 days (n = 6). Serum, liver, adipose and brains were collected and DHA levels and δ13C were determined. DHA concentrations were highest (p < 0.05) in the liver and adipose of DHA-fed animals with no diet differences in serum or brain (p > 0.05). Based on the presence or absence of overlapping 95 % C.I.'s, DHA half-lives and synthesis/turnover rates were not different between Ahiflower and DHA diets in the liver, adipose or brain. DHA half-lives and synthesis/turnover rates from flaxseed oil were significantly slower than from the DHA diet in all serum/tissues. These findings suggest that the distinct Ahiflower oil n-3 PUFA composition could support tissue DHA needs at a similar rate to dietary DHA, making it a unique plant-based dietary option for maintaining DHA turnover comparably to dietary DHA.

Dietary triacetin, but not medium chain triacylglycerides, blunts weight gain in diet-induced rat model of obesity.

Consumption of a Western diet (WD) is known to increase the risk of obesity. Short or medium chain fatty acids influence energy metabolism, and triacetin, a synthetic short chain triacylglyceride, has been shown to lower body fat under normal conditions. This study aimed to investigate if triacetin as part of a WD modifies rat weight and body fat. Male rats were fed a control diet or WD for 8 weeks. At week 8, rats in the WD group were maintained on a WD diet or switched to a WD diet containing 30% energy from medium-chain triacylglyceride (WD-MCT) or triacetin (WD-T) for another 8 weeks. At week 16, rats were euthanized and liver, adipose and blood were collected. Tissue fatty acids (FAs) were quantified by gas chromatography (GC) and hepatic FAs were measured by GC-combustion-isotope ratio mass spectrometry for δ13 C-palmitic acid (PAM)-a novel marker of de novo lipogenesis (DNL). Rats fed WD-T had a body weight not statistically different to the control group, and gained less body weight than rats fed WD alone. Furthermore, WD-T fed rats had a lower fat mass, and lower total liver and plasma FAs compared to the WD group. Rats fed WD-T did not differ from WD in blood ketone or glucose levels, however, had a significantly lower hepatic δ13 C-PAM value than WD fed rats; suggestive of lower DNL. In summary, we show that triacetin has the potential to blunt weight gain and adipose tissue accumulation in a rodent model of obesity, possibly due to a decrease in DNL.

Novel 13C enrichment technique reveals early turnover of DHA in peripheral tissues.

The brain is rich in DHA, which plays important roles in regulating neuronal function. Recently, using compound-specific isotope analysis that takes advantage of natural differences in carbon-13 content (13C/12C ratio or δ13C) of the food supply, we determined the brain DHA half-life. However, because of methodological limitations, we were unable to capture DHA turnover rates in peripheral tissues. In the current study, we applied compound-specific isotope analysis via high-precision GC combustion isotope ratio mass spectrometry to determine half-lives of brain, liver, and plasma DHA in mice following a dietary switch experiment. To model DHA tissue turnover rates in peripheral tissues, we added earlier time points within the diet switch study and took advantage of natural variations in the δ13C-DHA of algal and fish DHA sources to maintain DHA pool sizes and used an enriched (uniformly labeled 13C) DHA treatment. Mice were fed a fish-DHA diet (control) for 3 months, then switched to an algal-DHA treatment diet, the 13C enriched-DHA treatment diet, or they stayed on the control diet for the remainder of the study time course. In mice fed the algal and 13C enriched-DHA diets, the brain DHA half-life was 47 and 46 days, the liver half-life was 5.6 and 7.2 days, and the plasma half-life was 4.7 and 6.4 days, respectively. By using improved methodologies, we calculated DHA turnover rates in the liver and plasma, and our study for the first time, by using an enriched DHA source (very high δ13C), validated its utility in diet switch studies.

Serum lipid analysis and isotopic enrichment is suggestive of greater lipogenesis in young long-term cannabis users: A secondary analysis of a case-control study.

Cannabis is now legal in many countries and while numerous studies have reported on its impact on cognition and appetite regulation, none have examined fatty acid metabolism in young cannabis users. We conducted an exploratory analysis to evaluate cannabis impact on fatty acid metabolism in cannabis users (n = 21) and non-cannabis users (n = 16). Serum levels of some saturated and monounsaturated fatty acids, including palmitic, palmitoleic, and oleic acids were higher in cannabis users compared to nonusers. As palmitic acid can be derived from diet or lipogenesis from sugars, we evaluated lipogenesis using a de novo lipogenesis index (palmitate/linoleic acid) and carbon-specific isotope analysis, which allows for the determination of fatty acid 13 C signature. The significantly higher de novo lipogenesis index in the cannabis users group along with a more enriched 13 C signature of palmitic acid suggested an increase in lipogenesis. In addition, while serum glucose concentration did not differ between groups, pyruvate and lactate were lower in the cannabis user group, with pyruvate negatively correlating with palmitic acid. Furthermore, the endocannabinoid 2-arachidonoylglycerol was elevated in cannabis users and could contribute to lipogenesis by activating the cannabinoid receptor 1. Because palmitic acid has been suggested to increase inflammation, we measured peripheral cytokines and observed no changes in inflammatory cytokines. Finally, an anti-inflammatory metabolite of palmitic acid, palmitoylethanolamide was elevated in cannabis users. Our results suggest that lipogenic activity is increased in cannabis users; however, future studies, including prospective studies that control dietary intake are required.

The majority of brain palmitic acid is maintained by lipogenesis from dietary sugars and is augmented in mice fed low palmitic acid levels from birth.

Previously, results from studies investigating if brain palmitic acid (16:0; PAM) was maintained by either dietary uptake or de novo lipogenesis (DNL) varied. Here, we utilize naturally occurring carbon isotope ratios (13 C/12 C; δ13 C) to uncover the origin of brain PAM. Additionally, we explored brain and liver fatty acid concentration, brain metabolomics, and behavior. BALB/c dams were equilibrated onto either a low PAM diet (LP; <2%) or high PAM diet (HP; >95%) prior to producing one generation of offspring. Offspring stayed on the respective diet of the dam until 15-weeks of age, at which time the Open Field test was conducted, prior to euthanasia and tissue lipid extraction. Although liver PAM was lower in mice fed the LP diet, as well as female mice, brain PAM was not affected by diet or sex. Across mice of either sex on both diets, brain 13 C-PAM revealed compared to dietary uptake, DNL from dietary sugars contributed 68.8%-79.5% and 46.6%-58.0% to the total brain PAM pool by both peripheral and local brain DNL, and local brain DNL alone, respectively. DNL was augmented in mice fed the LP diet, and the ability to up-regulate DNL in the liver or the brain depended on sex. Anxiety-like behaviors were decreased in mice fed the LP diet and were correlated with markers of LP diet consumption including increased liver 13 C-PAM, warranting further investigation. Altogether, our results indicate that DNL from dietary sugars is a compensatory mechanism to maintain brain PAM in response to the LP diet.

Fatty acid dysregulation in the anterior cingulate cortex of depressed suicides with a history of child abuse.

Child abuse (CA) strongly increases the lifetime risk of suffering from major depression and predicts an unfavorable course for the illness. Severe CA has been associated with a specific dysregulation of oligodendrocyte function and thinner myelin sheaths in the human anterior cingulate cortex (ACC) white matter. Given that myelin is extremely lipid-rich, it is plausible that these findings may be accompanied by a disruption of the lipid profile that composes the myelin sheath. This is important to explore since the composition of fatty acids (FA) in myelin phospholipids can influence its stability, permeability, and compactness. Therefore, the objective of this study was to quantify and compare FA concentrations in postmortem ACC white matter in the choline glycerophospholipid pool (ChoGpl), a key myelin phospholipid pool, between adult depressed suicides with a history of CA (DS-CA) matched depressed suicides without CA (DS) and healthy non-psychiatric controls (CTRL). Total lipids were extracted from 101 subjects according to the Folch method and separated into respective classes using thin-layer chromatography. FA methyl esters from the ChoGpl fraction were quantified using gas chromatography. Our analysis revealed specific effects of CA in FAs from the arachidonic acid synthesis pathway, which was further validated with RNA-sequencing data. Furthermore, the concentration of most FAs was found to decrease with age. By extending the previous molecular level findings linking CA with altered myelination in the ACC, these results provide further insights regarding white matter alterations associated with early-life adversity.

A Scoping Review of Clinical Studies in Infants Fed Formulas Containing Palm Oil or Palm Olein and Sn-2 Palmitate.

BACKGROUND: Palmitic acid (PA; 16:0) is added to infant formula in the form of palm oil/palm olein (PO/POL) and stereospecific numbered-2 palmitate (SN2). Several studies have examined the effects of PO/POL and or SN2 in formulas on health outcomes, mainly growth, digestion, and absorption of nutrients. However, the roles of PA, PO/POL, and SN2 on neurodevelopment remains unknown. OBJECTIVES: The objective of this scoping review was to map out studies in infants fed formula with PO/POL or SN2 to identify current knowledge on the role of PA in infant nutrition, specifically neurodevelopment. METHODS: Data sources, including Medline, Embase, CAB Abstracts, and the Cochrane Database, were searched. Eligible articles were randomized controlled trials (RCTs) and observational studies examining outcomes in term singleton infants fed formula containing PO/POL or SN2. Studies examining preterm infants or infants with infections, mixed-feeding interventions, or outcomes not concerned with PO/POL or SN2 were excluded. Screening and data extraction were performed by 2 independent reviewers, and results were charted into 10 outcome categories. RESULTS: We identified 28 RCTs and 2 observational studies. Only 1 RCT examined a neurodevelopmental outcome, reporting infants fed SN2 formula had higher fine motor skill scores compared to those fed a vegetable oil formula with a lower amount of SN2; however, only after adjustment for maternal education and at an earlier, but not a later time point. Anthropometric measures do not appear to be influenced by PO/POL or SN2 within formulas. Alternatively, it was reported that infants fed PO/POL within formulas had a decreased absorption of calcium, total fat, and PA compared to those fed vegetable oil formulas. However, studies were heterogenous, making it difficult to isolate the effects of PO/POL or SN2 in formulas. CONCLUSIONS: Our review reiterates the need for future studies to address the effects of PO/POL and SN2 on neurodevelopment in infants. This study is registered at Open Science Framework as osf.io/697he.

Murine and human microglial cells are relatively enriched with eicosapentaenoic acid compared to the whole brain.

The brain is a multicellular organ enriched with lipids. While the fatty acid composition of gross cerebral tissue is well characterized, the fatty acid composition of specific brain cells, particularly microglia cells, is less well characterized. Microglia cells are the innate immune cells of the brain, and a paucity of studies measuring their fatty acid composition using either immortalized or primary microglia cells report a higher ratio of eicosapentaenoic acid (EPA) to docosahexaenoic acid (DHA) than widely observed in whole brain tissue. Here we further characterize the fatty acid composition of murine microglia cells from young male and female mice as well as of human origin and compared it with a myelin-enriched fraction from the same mice. Our results show that saturated and monounsaturated fatty acids are the most abundant followed by polyunsaturated fatty acids (PUFA), with no statistical differences between sexes. Regarding PUFA, although DHA levels did not differ between human and murine cells, EPA was statistically higher in murine microglia. Notably, the DHA to EPA ratio was about 400 times lower in microglial cells compared to the myelin-enriched fraction. Thus, our results suggest that as compared to whole brain tissue EPA is relatively abundant in microglia cells, particularly in comparison to other n-3 PUFA such as DHA. Since the fatty acid composition of microglia can influence their functionality, a better understanding of EPA and DHA metabolism in microglia and the brain could identify new targets to modify microglial activity.

Targeting innate immunity to protect and cure Alzheimer's disease: opportunities and pitfalls.

Innate immunity has been the focus of many new directions to understand the mechanisms involved in the aetiology of brain diseases, especially Alzheimer's disease (AD). AD is a multifactorial disorder, with the innate immune response and neuroinflammation at the forefront of the pathology. Thus, microglial cells along with peripheral circulating monocytes and more generally the innate immune response have been the target of several pre-clinical and clinical studies. More than a decade ago, inhibiting innate immune cells was considered to be the critical angle for preventing and treating brain diseases. After the failing of numerous clinical trials and the discovery that it may actually be the opposite in various pre-clinical models, the field has changed considerably. Here, we present both sides of the story with a particular emphasis on the beneficial properties of innate immune cells and how they can be targeted to have neuroprotective properties.

Selective Immunomodulatory and Neuroprotective Effects of a NOD2 Receptor Agonist on Mouse Models of Multiple Sclerosis.

The significance of monocytes has been demonstrated in multiple sclerosis (MS). One of the therapeutic challenges is developing medications that induce mild immunomodulation that is solely targeting specific monocyte subsets without affecting microglia. Muramyl dipeptide (MDP) activates the NOD2 receptor, and systemic MDP administrations convert Ly6Chigh into Ly6Clow monocytes. Here, we report selective immunomodulatory and therapeutic effects of MDP on cuprizone and experimental autoimmune encephalomyelitis (EAE) mouse models of MS. MDP treatment exerted various therapeutic effects in EAE, including delaying EAE onset and reducing infiltration of leukocytes into the CNS before EAE onset. Of great interest is the robust beneficial effect of the MDP treatment in mice already developing the disease several days after EAE onset. Finally, we found that the NOD2 receptor plays a critical role in MDP-mediated EAE resistance. Our results demonstrate that MDP is beneficial in both early and progressive phases of EAE. Based on these results, and upon comprehensive basic and clinical research, we anticipate developing NOD2 agonist-based medications for MS in the future.

The role of peripheral fatty acids as biomarkers for Alzheimer's disease and brain inflammation.

Alzheimer's disease (AD) is a complex and heterogeneous neurodegenerative disease. A wide range of techniques have been proposed to facilitate early diagnosis of AD, including biomarkers from the cerebrospinal fluid and blood. Although phosphorylated tau and amyloid beta are amongst the most promising biomarkers of AD, other peripheral biomarkers have been identified and in this review we synthesize the current knowledge on circulating fatty acids. Fatty acids are involved in different biological process including neurotransmission and inflammation. Interestingly, some fatty acids appear to be modulated during disease progression, including long chain saturated fatty acids, and polyunsaturated fatty acids, such as docosahexaenoic acid . However, discrepant results have been reported in the literature and there is the need for further validation and method standardization. Nonetheless, our literature review suggests that fatty acid analyses could potentially provide a valuable source of data to further inform the pathology and progression of AD.

Baseline omega-3 level is associated with nerve regeneration following 12-months of omega-3 nutrition therapy in patients with type 1 diabetes.

AIM: Omega-3 (n-3) polyunsaturated fatty-acids are essential for the development and maintenance of nerve function, but the relationship of plasma n-3 to the presence of diabetic distal-symmetric-polyneuropathy (DSP) and the effect of n-3 therapy on plasma levels and small nerve fibre morphology in T1D are unknown. METHODS: Participants with T1D (n = 40, 53% female, aged (mean ±â€¯SD) 48 ±â€¯14 years, BMI 28.1 ±â€¯5.8 kg/m2, diabetes duration 27 ±â€¯18 years), 23 of whom had DSP, took seal-oil (10 mL/day; 750 mg eicosapentaenoic acid (EPA), 560 mg docosapentaenoic acid (DPAn-3), and 1020 mg docosahexaenoic acid (DHA)) for 12-months in a single-arm open-label study. The improvement in corneal nerve fibre length (CNFL) (primary outcome) was previously reported. In this secondary analysis, plasma n-3s were measured at baseline, 4, 8 and 12-months. RESULTS: At baseline, participants with DSP had lower DHA than those without (1.73 ±â€¯0.89 vs. 2.27 ±â€¯0.70%, p = 0.049). Twelve-months seal-oil therapy increased mean plasma EPA by 185%, DPA by 29%, DHA by 79% (p < 0.001) and CNFL by 29% (p = 0.001). Change in CNFL was positively associated with higher baseline total n-3 (Spearman's correlation coefficient r = 0.41, p = 0.013), DPA (r = 0.33, p = 0.047) and DHA (r = 0.42, p = 0.012). CONCLUSION: In conclusion, low plasma DHA was associated with prevalent DSP, n-3 therapy increased blood n-3 levels and higher baseline n-3s were associated with greater nerve regeneration.

The Intellicage system provides a reproducible and standardized method to assess behavioral changes in cuprizone-induced demyelination mouse model.

BACKGROUND: Multiple sclerosis is a neurodegenerative disorder characterized by myelin loss in the brain parenchyma. To mimic the disease, mice are fed a cuprizone-supplemented diet for 5 weeks, which leads to demyelination of white and grey matter regions, with the corpus callosum being the most susceptible to cuprizone intoxication. Although this model is highly exploited, classical behavioural tests showed inconsistent results. OBJECTIVE: In our study, we aimed to use the automated system Intellicage to phenotype the behaviour of cuprizone-fed mice. METHODS: Mice were continuously monitored during the 5 weeks of intoxication in their home cages, with minimal interference from the experimenter. Mice were assessed for spontaneous activity, fine movements, and impulsivity. RESULTS: Consistently, cuprizone-fed mice showed reduced activity and impulsivity throughout the test period. These behavioral results were confirmed by repeating the battery of behavioral tests in a second cohort of cuprizone-fed mice. Our results suggest that the behavioural phenotyping of cuprizone-fed mice using Intellicage is reproducible and sensitive enough to detect changes normally missed in standard behavioral test batteries. CONCLUSION: Using a reproducible and standardized method to assess behavioral changes in mice intoxicated with cuprizone is crucial to better understand the disease as well as the functional outcome of treatments.

Muramyl dipeptide-mediated immunomodulation on monocyte subsets exerts therapeutic effects in a mouse model of Alzheimer's disease.

BACKGROUND: Muramyl dipeptide (MDP) is a component derived from minimal peptidoglycan motif from bacteria, and it is a ligand for the NOD2 receptor. Peripheral administration of MDP converts Ly6Chigh into Ly6Clow monocytes. Previously, we have shown that Ly6Clow monocytes play crucial roles in the pathology of a mouse model of Alzheimer's disease (AD). However, medications with mild immunomodulatory effects that solely target specific monocyte subsets, without triggering microglial activation, are rare. METHODS: Three months old APPswe/PS1 transgenic male mice and age-matched C57BL/6 J mice were used for high frequency (2 times/week) over 6 months and low frequency (once a week) over 3 months of intraperitoneally MDP (10 mg/kg) administrations. Flow cytometry analysis of monocyte subsets in blood, and behavioral and postmortem analyses were performed. RESULTS: Memory tests showed mild to a strong improvement in memory function, increased expression levels of postsynaptic density protein 95 (PSD95), and low-density lipoprotein receptor-related protein 1 (LRP1), which are involved in synaptic plasticity and amyloid-beta (Aß) elimination, respectively. In addition, we found monocyte chemoattractant protein-1(MCP-1) levels significantly increased, whereas intercellular adhesion molecule-1(ICAM-1) significantly decreased, and microglial marker (Iba1) did not change in the treatment group compared to the control. In parallel, we discovered elevated cyclooxygenase-2 (COX2) expression levels in the treated group, which might be a positive factor for synaptic activity. CONCLUSIONS: Our results demonstrate that MDP is beneficial in both the early phase and, to some extent, later phases of the pathology in the mouse model of AD. These data open the way for potential MDP-based medications for AD.

Use of adeno-associated virus-mediated delivery of mutant huntingtin to study the spreading capacity of the protein in mice and non-human primates.

In order to model various aspects of Huntington's disease (HD) pathology, in particular protein spread, we administered adeno-associated virus (AAV) expressing green fluorescent protein (GFP) or GFP coupled to HTT-Exon1 (19Q or 103Q) to the central nervous system of adult wild-type (WT) mice and non-human primates. All animals underwent behavioral testing and post-mortem analyses to determine the long-term consequences of AAV injection. Both mice and non-human primates demonstrated behavioral changes at 2-3 weeks post-surgery. In mice, these changes were absent after 3 months while in non-human primates, they persisted in the majority of tested animals. Post-mortem analysis revealed that spreading of the aggregates was limited, although the virus did spread between synaptically-connected brain regions. Despite circumscribed spreading, the presence of mHTT generated changes in endogenous huntingtin (HTT) levels in both models. Together, these results suggest that viral expression of mHTTExon1 can induce spreading and seeding of HTT in both mice and non-human primates.