Amyloid Beta Transport and Effects on Permeability in a Human Brain Endothelial Cell Line

The clearance of neurotoxic amyloid beta (Aβ) from the brain represents a novel therapeutic target for Alzheimer's disease (AD). The ability of two blood-brain barrier (BBB) drug transporters, P-glycoprotein (P-gp) and the breast cancer resistance protein (BCRP), to transport Aβ was investigated using a human brain endothelial cell (BEC) line, hCMEC/D3. P-gp expression by hCMEC/D3 cells was stable over a high passage number, polarised on the apical membrane, consistent with the blood side in vivo, and comparable, albeit slightly reduced, to primary isolated human BECs. The P-gp inhibitors tariquidar and vinblastine prevented the efflux of rhodamine 123 from hCMEC/D3 cells, indicative of functional P-gp expression. hCMEC/D3 cells therefore constituted a suitable model to investigate P-gp substrate interactions in vitro. P-gp, and to a lesser extent BCRP, inhibition, increased the net influx and decreased the efflux of 0.1 nM 125I Aβ 1-40 in hCMEC/D3 cells. Both P-gp and BCRP inhibition increased the apical-to-basolateral but not the basolateral-to-apical permeability of hCMEC/D3 cells to 125I Aβ 1-40. This data is consistent with P-gp and BCRP, acting in vivo to prevent blood-borne Aβ peptides entering the brain but not to clear Aβ load from the brain. Vascular dysfunction is emerging as a key pathological hallmark in AD, including increased BBB permeability. The effect of Aβ on the permeability of hCMEC/D3 cells was therefore investigated. Aβ 1-40 induced a marked increase in hCMEC/D3 cell permeability to the paracellular tracer 70 kDa FITC-dextran. Increased permeability was associated with a specific decrease in the tight junction protein occludin, but not claudin-5 or ZO-1, both at the protein and mRNA levels. JNK and p38MAPK inhibition prevented Aβ 1-40-mediated occludin down-regulation and increased paracellular permeability of hCMEC/D3 cells. Our findings suggest that the JNK and p38MAPK pathways might represent attractive therapeutic targets for preventing vascular dysfunction in AD

Fault-tolerant communication channel structures

Systems and techniques for implementing fault-tolerant communication channels and features in communication systems. Selected commercial-off-the-shelf devices can be integrated in such systems to reduce the cost

Introducing Human APOE into Aβ Transgenic Mouse Models

Apolipoprotein E (apoE) and apoE/amyloid-β (Aβ) transgenic (Tg) mouse models are critical to understanding apoE-isoform effects on Alzheimer's disease risk. Compared to wild type, apoE−/− mice exhibit neuronal deficits, similar to apoE4-Tg compared to apoE3-Tg mice, providing a model for Aβ-independent apoE effects on neurodegeneration. To determine the effects of apoE on Aβ-induced neuropathology, apoE−/− mice were crossed with Aβ-Tg mice, resulting in a significant delay in plaque deposition. Surprisingly, crossing human-apoE-Tg mice with apoE−/−/Aβ-Tg mice further delayed plaque deposition, which eventually developed in apoE4/Aβ-Tg mice prior to apoE3/Aβ-Tg. One approach to address hAPOE-induced temporal delay in Aβ pathology is an additional insult, like head injury. Another is crossing human-apoE-Tg mice with Aβ-Tg mice that have rapid-onset Aβ pathology. For example, because 5xFAD mice develop plaques by 2 months, the prediction is that human-apoE/5xFAD-Tg mice develop plaques around 6 months and 12 months before other human-apoE/Aβ-Tg mice. Thus, tractable models for human-apoE/Aβ-Tg mice continue to evolve

Soluble apoE/Aβ complex: mechanism and therapeutic target for APOE4-induced AD risk

The APOE4 allele of apolipoprotein E (apoE) is the greatest genetic risk factor for Alzheimer\u27s disease (AD) compared to APOE2 and APOE3. Amyloid-β (Aβ), particularly in a soluble oligomeric form (oAβ), is considered a proximal cause of neurodegeneration in AD. Emerging data indicate that levels of soluble oAβ are increased with APOE4, providing a potential mechanism of APOE4-induced AD risk. However, the pathway(s) by which apoE4 may increase oAβ levels are unclear and the subject of continued inquiry. In this editorial review, we present the hypothesis that apoE isoform-specific interactions with Aβ, namely apoE/Aβ complex, modulate Aβ levels. Specifically, we propose that compared to apoE3, apoE4-containing lipoproteins are less lipidated, leading to less stable apoE4/Aβ complexes, resulting in reduced apoE4/Aβ levels and increased accumulation, particularly of oAβ. Evidence that support or counter this argument, as well as the therapeutic significance of this pathway to neurodegeneration, are discussed

Peripheral Inflammation, \u3cem\u3eApolipoprotein E4\u3c/em\u3e, and Amyloid-β Interact to Induce Cognitive and Cerebrovascular Dysfunction

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

Soluble apoE/Aβ Complex: Mechanism and Therapeutic target for APOE4-induced AD Risk

The APOE4 allele of apolipoprotein E (apoE) is the greatest genetic risk factor for Alzheimer\u27s disease (AD) compared to APOE2 and APOE3. Amyloid-β (Aβ), particularly in a soluble oligomeric form (oAβ), is considered a proximal cause of neurodegeneration in AD. Emerging data indicate that levels of soluble oAβ are increased with APOE4, providing a potential mechanism of APOE4-induced AD risk. However, the pathway(s) by which apoE4 may increase oAβ levels are unclear and the subject of continued inquiry. In this editorial review, we present the hypothesis that apoE isoform-specific interactions with Aβ, namely apoE/Aβ complex, modulate Aβ levels. Specifically, we propose that compared to apoE3, apoE4-containing lipoproteins are less lipidated, leading to less stable apoE4/Aβ complexes, resulting in reduced apoE4/Aβ levels and increased accumulation, particularly of oAβ. Evidence that support or counter this argument, as well as the therapeutic significance of this pathway to neurodegeneration, are discussed

Feasibility of Deploying Home-Based Digital Technology, Environmental Sensors, and Web-Based Surveys for Assessing Behavioral Symptoms and Identifying Their Precipitants in Older Adults: Longitudinal, Observational Study.

Apathy, depression, and anxiety are prevalent neuropsychiatric symptoms experienced by older adults. Early detection, prevention, and intervention may improve outcomes

Exercise training results in lower amyloid plaque load and greater cognitive function in an intensity dependent manner in the Tg2576 mouse model of Alzheimer\u27s disease

Three months of exercise training (ET) decreases soluble A

Genetics Ignite Focus on Microglial Inflammation in Alzheimer\u27s Disease

In the past five years, a series of large-scale genetic studies have revealed novel risk factors for Alzheimer\u27s disease (AD). Analyses of these risk factors have focused attention upon the role of immune processes in AD, specifically microglial function. In this review, we discuss interpretation of genetic studies. We then focus upon six genes implicated by AD genetics that impact microglial function: TREM2, CD33, CR1, ABCA7, SHIP1, and APOE. We review the literature regarding the biological functions of these six proteins and their putative role in AD pathogenesis. We then present a model for how these factors may interact to modulate microglial function in AD