The ε4 allele of the apolipoprotein E gene (APOE4) is associated with cognitive decline during aging, is the greatest genetic risk factor for Alzheimer’s disease and has links to other neurodegenerative conditions that affect cognition. Increasing evidence indicates that APOE genotypes differentially modulate the function of the cerebrovasculature (CV), with apoE and its receptors expressed by different cell types at the CV interface (astrocytes, pericytes, smooth muscle cells, brain endothelial cells). However, research on the role of apoE in CV dysfunction has not advanced as quickly as other apoE-modulated pathways. This review will assess what aspects of the CV are modulated by APOE genotypes during aging and under disease states, discuss potential mechanisms, and summarize the therapeutic significance of the topic. We propose that APOE4 induces CV dysfunction through direct signaling at the CV, and indirectly via modulation of peripheral and central pathways. Further, that APOE4 predisposes the CV to damage by, and exacerbates the effects of, additional risk factors (such as sex, hypertension, and diabetes). ApoE4-induced detrimental CV changes include reduced cerebral blood flow (CBF), modified neuron-CBF coupling, increased blood-brain barrier leakiness, cerebral amyloid angiopathy (CAA), hemorrhages and disrupted transport of nutrients and toxins. The apoE4-induced detrimental changes may be linked to pericyte migration/activation, astrocyte activation, smooth muscle cell damage, basement membrane degradation and alterations in brain endothelial cells.

Docosahexaenoic acid (DHA) is uniquely concentrated in the brain, and is essential for its function, but must be mostly acquired from diet. Most of the current supplements of DHA, including fish oil and krill oil, do not significantly increase brain DHA, because they are hydrolyzed to free DHA and are absorbed as triacylglycerol, whereas the transporter at blood brain barrier is specific for phospholipid form of DHA. Here we show that oral administration of DHA to normal adult mice as lysophosphatidylcholine (LPC) (40 mg DHA/kg) for 30 days increased DHA content of the brain by >2-fold. In contrast, the same amount of free DHA did not increase brain DHA, but increased the DHA in adipose tissue and heart. Moreover, LPC-DHA treatment markedly improved the spatial learning and memory, as measured by Morris water maze test, whereas free DHA had no effect. The brain derived neurotrophic factor increased in all brain regions with LPC-DHA, but not with free DHA. These studies show that dietary LPC-DHA efficiently increases brain DHA content and improves brain function in adult mammals, thus providing a novel nutraceutical approach for the prevention and treatment of neurological diseases associated with DHA deficiency, such as Alzheimer's disease. Docosahexaenoic acid (DHA), an essential omega 3 fatty acid, is uniquely concentrated in the brain, nervous tissues and retina, and is essential for the normal neurological development and function. The deficiency of DHA is associated with several neurological disorders, including Alzheimer's, Parkinson's, schizophrenia, and depression [1][2][3][4][5] . Unlike liver, the brain cannot efficiently convert dietary alpha linolenic acid (18:3, n-3) to DHA 6,7 , and is almost completely dependent upon the uptake of preformed DHA from the plasma. However, dietary supplementation with the currently available preparations of DHA such as fish or krill oil 8 , algal DHA 9 , DHA-enriched egg phospholipids 10 ethyl esters 11 and sardines 12 does not appreciably increase brain DHA levels in adult mammals, although peripheral tissues are enriched with DHA under the same conditions. One possible explanation for this is that DHA from the above supplements is hydrolyzed to free DHA by the pancreatic enzymes and absorbed as triacylglycerol (TAG) in chylomicrons (Fig. 1), whereas the brain uniquely takes up DHA in the form of lysophosphatidylcholine (LPC) [13][14][15] . The recent demonstration of a transporter at the blood brain barrier (Mfsd2a), which specifically transports LPC-DHA, but not free DHA 16, further supports this mechanism. It is therefore necessary to increase the levels of LPC-DHA in plasma for an efficient enrichment of brain DHA. We propose that if dietary DHA is provided in the sn-1 position of phosphatidylcholine (PC) or in the form of LPC in the diet, it should escape the hydrolysis by pancreatic PLA 2 , and will be absorbed as PC-DHA (Fig. 1). The PC-DHA is more likely to be taken up by the brain after conversion to LPC-DHA in plasma or liver by the phospholipases, compare...

Cerebrovascular (CV) dysfunction is emerging as a critical component of Alzheimer’s disease (AD), including altered CV coverage. Angiogenic growth factors (AGFs) are key for controlling CV coverage, especially during disease pathology. Therefore, evaluating the effects of AGFs in vivo can provide important information on the role of CV coverage in AD. We recently demonstrated that epidermal growth factor (EGF) prevents amyloid-beta (Aβ)-induced damage to brain endothelial cells in vitro. Here, our goal was to assess the protective effects of EGF on cognition, CV coverage and Aβ levels using an AD-Tg model that incorporates CV relevant AD risk factors. APOE4 is the greatest genetic risk factor for sporadic AD especially in women and is associated with CV dysfunction. EFAD mice express human APOE3 (E3FAD) or APOE4 (E4FAD), overproduce human Aβ42 and are a well characterized model of APOE pathology. Thus, initially the role of APOE and sex in cognitive and CV dysfunction was assessed in EFAD mice in order to identify a group for EGF treatment. At 8 months E4FAD female mice were cognitively impaired, had low CV coverage, high microbleeds and low plasma EGF levels. Therefore, E4FAD female mice were selected for an EGF prevention paradigm (300 μg/kg/wk, 6 to 8.5 months). EGF prevented cognitive decline and was associated with lower microbleeds and higher CV coverage, but not changes in Aβ levels. Collectively, these data suggest that EGF can prevent Aβ-induced damage to the CV. Developing therapeutic strategies based on AGFs may be particularly efficacious for APOE4-induced AD risk.Electronic supplementary materialThe online version of this article (doi:10.1186/s40478-016-0387-3) contains supplementary material, which is available to authorized users.

Cerebrovascular dysfunction is rapidly reemerging as a major process of Alzheimer’s disease (AD). It is, therefore, crucial to delineate the roles of AD risk factors in cerebrovascular dysfunction. While apolipoprotein E4 (APOE4), Amyloid-β (Aβ), and peripheral inflammation independently induce cerebrovascular damage, their collective effects remain to be elucidated. The goal of this study was to determine the interactive effect of APOE4, Aβ, and chronic repeated peripheral inflammation on cerebrovascular and cognitive dysfunction in vivo. EFAD mice are a well-characterized mouse model that express human APOE3 (E3FAD) or APOE4 (E4FAD) and overproduce human Aβ42 via expression of 5 Familial Alzheimer’s disease (5xFAD) mutations. Here, we utilized EFAD carriers [5xFAD+/−/APOE+/+ (EFAD+)] and noncarriers [5xFAD−/−/APOE+/+ (EFAD−)] to compare the effects of peripheral inflammation in the presence or absence of human Aβ overproduction. Low-level, chronic repeated peripheral inflammation was induced in EFAD mice via systemic administration of lipopolysaccharide (LPS; 0.5 mg/kg/wk i.p.) from 4 to 6 months of age. In E4FAD+ mice, peripheral inflammation caused cognitive deficits and lowered post-synaptic protein levels. Importantly, cerebrovascular deficits were observed in LPS-challenged E4FAD+ mice, including cerebrovascular leakiness, lower vessel coverage, and cerebral amyloid angiopathy-like Aβ deposition. Thus, APOE4, Aβ, and peripheral inflammation interact to induce cerebrovascular damage and cognitive deficits.

Identified in 1993, is the greatest genetic risk factor for sporadic Alzheimer's disease (AD), increasing risk up to 15-fold compared with, with decreasing AD risk. However, the functional effects of on AD pathology remain unclear and, in some cases, controversial. In vivo progress to understand how the human (h)- genotypes affect AD pathology has been limited by the lack of a tractable familial AD-transgenic (FAD-Tg) mouse model expressing h- rather than mouse (m)- The disparity between m- and h-apoE is relevant for virtually every AD-relevant pathway, including amyloid-β (Aβ) deposition and clearance, neuroinflammation, tau pathology, neural plasticity and cerebrovascular deficits. EFAD mice were designed as a temporally useful preclinical FAD-Tg-mouse model expressing the h- genotypes for identifying mechanisms underlying -modulated symptoms of AD pathology. From their first description in 2012, EFAD mice have enabled critical basic and therapeutic research. Here we review insights gleaned from the EFAD mice and summarize future directions.