ScopeCurrently available omega‐3 fatty acid supplements do not enrich the docosahexaenoic acid (DHA) of the adult brain because they are absorbed as triacylglycerol, whereas the transporter at the blood brain barrier requires lysophosphatidylcholine (LPC)‐DHA. The hypothesis that treatment of krill oil (KO), which contains DHA/eicosapentaenoic acid (EPA) at the SN2 position of phosphatidylcholine, with SN1‐specific lipase will generate LPC‐DHA/EPA and which can be absorbed intact and transported into the brain, is tested.MethodsKO and fish oil (FO) are treated with Mucor meihei lipase, incorporated into AIN 93G diet, and fed to 2‐month‐old mice for 30 days. Fatty acid composition is analyzed by gas chromatography/mass spectroscopy. Brain derived neurotrophic factor (BDNF) is measured by ELISA.ResultsLipase‐treated (LT) KO increases brain DHA and EPA, respectively, 5‐and 70‐fold better than untreated (UT) KO. FO, whether lipase‐treated or not, has no effect on brain DHA/EPA. LTKO is also more efficient in enriching liver DHA/EPA, but less efficient than UTKO and FO in enriching adipose tissue and heart. Brain BDNF is significantly increased by LTKO, but only marginally by other preparations.ConclusionsPretreatment of dietary KO with lipase enables it to efficiently increase brain DHA/EPA because of the generation of LPC‐DHA/EPA.

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APOE4 is a major genetic risk factor for Alzheimer's disease and high amyloid-β (Aβ) levels in the brain are a pathological hallmark of the disease. However, the contribution of specific APOE-modulated Aβ-dependent and Aβ-independent functions to cognitive decline remain unclear. Increasing evidence supports a role of APOE in modulating cerebrovascular function, however whether ameliorating this dysfunction can improve behavioral function is still under debate. We have previously demonstrated that systemic epidermal growth factor (EGF) treatment, which is important for vascular function, at early stages of pathology (treatment from 6 to 8 months) is beneficial for recognition and spatial memory and cerebrovascular function in female mice that express APOE4. These data raise the important question of whether EGF can improve APOE4-associated cerebrovascular and behavioral dysfunction when treatment is initiated at an age of advanced pathology. Positive findings would support the development of therapies that target cerebrovascular dysfunction associated with APOE4 in aging and AD in individuals with advanced cognitive impairment. Therefore, in this study female mice that express APOE4 in the absence (E4FAD-mice) or presence (E4FADþ mice) of Aβ overproduction were treated from 8 to 10 months of age systemically with EGF. EGF treatment mitigated behavioral dysfunction in recognition memory and spatial learning and improved hippocampal neuronal function in both E4FADþ and E4FAD-mice, suggesting that EGF treatment improves Aβ-independent APOE4-associated deficits. The beneficial effects of EGF treatment on behavior occurred in tandem with improved markers of cerebrovascular function, including lower levels of fibrinogen, lower permeability when assessed by MRI and higher percent area coverage of laminin and CD31 in the hippocampus. These data suggest a mechanistic link among EGF signaling, cerebrovascular function and APOE4-associated behavioral deficits in mice with advanced AD-relevant pathology.

Krabbe Disease (KD) is a lysosomal storage disorder characterized by the genetic deficiency of the lysosomal enzyme β-galactosyl-ceramidase (GALC). Deficit or a reduction in the activity of the GALC enzyme has been correlated with the progressive accumulation of the sphingolipid metabolite psychosine, which leads to local disruption in lipid raft architecture, diffuse demyelination, astrogliosis, and globoid cell formation. The twitcher mouse, the most used animal model, has a nonsense mutation, which limits the study of how different mutations impact the processing and activity of GALC enzyme. To partially address this, we generated two new transgenic mouse models carrying point mutations frequently found in infantile and adult forms of KD. Using CRISPR-Cas9 gene editing, point mutations T513M (infantile) and G41S (adult) were introduced in the murine GALC gene and stable founders were generated. We show that GALCT513M/T513M mice are short lived, have the greatest decrease in GALC activity, have sharp increases of psychosine, and rapidly progress into a severe and lethal neurological phenotype. In contrast, GALCG41S/G41S mice have normal lifespan, modest decreases of GALC, and minimal psychosine accumulation, but develop adult mild inflammatory demyelination and slight declines in coordination, motor skills, and memory. These two novel transgenic lines offer the possibility to study the mechanisms by which two distinct GALC mutations affect the trafficking of mutated GALC and modify phenotypic manifestations in early- vs adult-onset KD.

Evidence suggests that angiotensin receptor blockers (ARBs) could be beneficial for Alzheimer’s disease (AD) patients independent of any effects on hypertension. However, studies in rodent models directly testing the activity of ARB treatment on behavior and AD-relevent pathology including neuroinflammation, Aβ levels, and cerebrovascular function, have produced mixed results. APOE4 is a major genetic risk factor for AD and has been linked to many of the same functions as those purported to be modulated by ARB treatment. Therefore, evaluating the effects of ARB treatment on behavior and AD-relevant pathology in mice that express human APOE4 could provide important information on whether to further develop ARBs for AD therapy. In this study, we treated female and male mice that express the human APOE4 gene in the absence (E4FAD−) or presence (E4FAD+) of high Aβ levels with the ARB prodrug candesartan cilexetil for a duration of 4 months. Compared to vehicle, candesartan treatment resulted in greater memory-relevant behavior and higher hippocampal presynaptic protein levels in female, but not male, E4FAD− and E4FAD+ mice. The beneficial effects of candesartan in female E4FAD− and E4FAD+ mice occurred in tandem with lower GFAP and Iba1 levels in the hippocampus, whereas there were no effects on markers of cerebrovascular function and Aβ levels. Collectively, these data imply that the effects of ARBs on AD-relevant pathology may be modulated in part by the interaction between APOE genotype and biological sex. Thus, the further development of ARBs could provide therapeutic options for targeting neuroinflammation in female APOE4 carriers.