Neuroinflammation is proposed as one of the mechanisms by which Alzheimer’s disease pathology, including amyloid-β plaques, leads to neuronal death and dysfunction. Increases in the expression of markers of microglia, the main neuroinmmune cell, are widely reported in brains from patients with Alzheimer’s disease, but the literature has not yet been systematically reviewed to determine whether this is a consistent pathological feature. A systematic search was conducted in Medline, Embase and PsychINFO for articles published up to 23 February 2017. Papers were included if they quantitatively compared microglia markers in post-mortem brain samples from patients with Alzheimer’s disease and aged controls without neurological disease. A total of 113 relevant articles were identified. Consistent increases in markers related to activation, such as major histocompatibility complex II (36/43 studies) and cluster of differentiation 68 (17/21 studies), were identified relative to nonneurological aged controls, whereas other common markers that stain both resting and activated microglia, such as ionized calcium-binding adaptor molecule 1 (10/20 studies) and cluster of differentiation 11b (2/5 studies), were not consistently elevated. Studies of ionized calcium-binding adaptor molecule 1 that used cell counts almost uniformly identified no difference relative to control, indicating that increases in activation occurred without an expansion of the total number of microglia. White matter and cerebellum appeared to be more resistant to these increases than other brain regions. Nine studies were identified that included high pathology controls, patients who remained free of dementia despite Alzheimer’s disease pathology. The majority (5/9) of these studies reported higher levels of microglial markers in Alzheimer’s disease relative to controls, suggesting that these increases are not solely a consequence of Alzheimer’s disease pathology. These results show that increased markers of microglia are a consistent feature of Alzheimer’s disease, though this seems to be driven primarily by increases in activation-associated markers, as opposed to markers of all microglia.

DHA (22:6n-3) may be derived from two dietary sources, preformed dietary DHA or through synthesis from α-linolenic acid (ALA; 18:3n-3). However, conventional methods cannot distinguish between DHA derived from either source without the use of costly labeled tracers. In the present study, we demonstrate the proof-of-concept that compound-specific isotope analysis (CSIA) by GC-isotope ratio mass spectrometry (IRMS) can differentiate between sources of brain DHA based on differences in natural C enrichment. Mice were fed diets containing either purified ALA or DHA as the sole n-3 PUFA. Extracted lipids were analyzed by CSIA for natural abundanceC enrichment. Brain DHA from DHA-fed mice was significantly more enriched (-23.32‰ to -21.92‰) compared with mice on the ALA diet (-28.25‰ to -27.49‰). The measured C enrichment of brain DHA closely resembled the dietary n-3 PUFA source, -21.86‰ and -28.22‰ for DHA and ALA, respectively. The dietary effect on DHAC enrichment was similar in liver and blood fractions. Our results demonstrate the effectiveness of CSIA, at natural C enrichment, to differentiate between the incorporation of preformed or synthesized DHA into the brain and other tissues without the need for tracers.

BackgroundNeuroinflammation is a proposed mechanism by which Alzheimer’s disease (AD) pathology potentiates neuronal death and cognitive decline. Consumption of omega-3 polyunsaturated fatty acids (PUFA) is associated with a decreased risk of AD in human observational studies and exerts protective effects on cognition and pathology in animal models. These fatty acids and molecules derived from them are known to have anti-inflammatory and pro-resolving properties, presenting a potential mechanism for these protective effects.MethodsHere, we explore this mechanism using fat-1 transgenic mice and their wild type littermates weaned onto either a fish oil diet (high in n-3 PUFA) or a safflower oil diet (negligible n-3 PUFA). The fat-1 mouse carries a transgene that enables it to convert omega-6 to omega-3 PUFA. At 12 weeks of age, mice underwent intracerebroventricular (icv) infusion of amyloid-β 1-40. Brains were collected between 1 and 28 days post-icv, and hippocampal microglia, astrocytes, and degenerating neurons were quantified by immunohistochemistry with epifluorescence microscopy, while microglia morphology was assessed with confocal microscopy and skeleton analysis.ResultsFat-1 mice fed with the safflower oil diet and wild type mice fed with the fish oil diet had higher brain DHA in comparison with the wild type mice fed with the safflower oil diet. Relative to the wild type mice fed with the safflower oil diet, fat-1 mice exhibited a lower peak in the number of labelled microglia, wild type mice fed with fish oil had fewer degenerating neurons, and both exhibited alterations in microglia morphology at 10 days post-surgery. There were no differences in astrocyte number at any time point and no differences in the time course of microglia or astrocyte activation following infusion of amyloid-β 1-40.ConclusionsIncreasing brain DHA, through either dietary or transgenic means, decreases some elements of the inflammatory response to amyloid-β in a mouse model of AD. This supports the hypothesis that omega-3 PUFA may be protective against AD by modulating the immune response to amyloid-β.

Saturated fatty acids are the most abundant fatty acids in the brain, however, there has been some debate regarding the ability of intact dietary saturated fatty acids to be incorporated into the brain. In the present study, we use compound specific isotope analysis to measure the natural abundance carbon isotopic signature of brain, liver, and blood palmitic acid (PAM) and compare it to the dietary PAM and sugar isotopic signatures to calculate the relative contribution of both the incorporation of intact and endogenously synthesized PAM to these pools. Mice were equilibrated to the study diet, and extracted fatty acids were analyzed with gas chromatography isotope ratio mass spectrometry to determine the carbon isotopic signature of PAM (δ C ). Liver, serum total, and serum unesterified fatty acid δ C ranged between -20.6 and -21.1 mUr and were approximately 8.5 mUr more enriched in C when compared to the dietary PAM signature. Brain δ C was found to be more enriched than liver or blood pools (-16.7 ± 0.2 mUr, mean ± SD). Two end-member-mixed modeling using the carbon isotopic signature of dietary PAM and dietary sugars determined the contribution of synthesis to the total tissue PAM pool to range between 44% and 48%. This suggests that endogenous synthesis and dietary PAM are near equal contributors to brain, liver, and blood PAM pools. In conclusion, our data provide evidence that brain PAM levels are maintained by both local endogenous synthesis and through the uptake of intact PAM from the blood.

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