APOE4 is the strongest genetic risk factor for late-onset Alzheimer’s disease (AD). ApoE4 increases brain amyloid-β (Aβ) pathology relative to other ApoE isoforms1. However, whether APOE independently influences tau pathology, the other major proteinopathy of AD and other tauopathies, or tau-mediated neurodegeneration, is not clear. By generating P301S tau transgenic mice on either a human ApoE knockin (KI) or ApoE knockout (KO) background, we show that P301S/E4 mice have significantly higher tau levels in the brain and a greater extent of somatodendritic tau redistribution by 3 months of age compared to P301S/E2, P301S/E3 and P301S/EKO mice. By 9 months of age, P301S mice with different ApoE genotypes display distinct p-tau staining patterns. P301S/E4 mice develop markedly more brain atrophy and neuroinflammation than P301S/E2 and P301S/E3 mice, whereas P301S/EKO mice are largely protected from these changes. In vitro, E4-expressing microglia exhibit higher innate immune reactivity following LPS treatment. Co-culturing P301S tau-expressing neurons with E4-expressing mixed glia results in a significantly higher level of TNFα secretion and markedly reduced neuronal viability compared to neuron/E2 and neuron/E3 co-cultures. Neurons co-cultured with EKO glia showed the greatest viability with the lowest level of secreted TNFα. Treatment of P301S neurons with recombinant ApoE (E2, E3, E4) also leads to some neuronal damage and death compared to the absence of ApoE, with ApoE4 exacerbating the effect. In individuals with a sporadic primary tauopathy, the presence of an ε4 allele is associated with more severe regional neurodegeneration. In Aβ-pathology positive individuals with symptomatic AD who usually have tau pathology, ε4-carriers demonstrate greater rates of disease progression. Our results demonstrate that ApoE affects tau pathogenesis, neuroinflammation, and tau-mediated neurodegeneration independent of Aβ pathology. ApoE4 exerts a “toxic” gain of function whereas the absence of ApoE is protective.

Two porous covalent organic frameworks (COFs) with good biocompatibility were employed as drug nanocarriers, where three different drugs were loaded for subsequent drug release in vitro. The present work demonstrates that COFs are applicable in drug delivery for therapeutic applications.

The investigation on the formation mechanism of helical structures and the synthesis of helical materials is attractive for scientists in different fields. Here we report the synthesis of helical mesoporous materials with chiral channels in the presence of achiral surfactants. More importantly, we suggest a simple and purely interfacial interaction mechanism to explain the spontaneous formation of helical mesostructures. Unlike the proposed model for the formation of helical molecular chains or surpramolecular packing based on the geometrically motivated model or the entropically driven model, the origin of the helical mesostructured materials may be attributed to a morphological transformation accompanied by a reduction in surface free energy. After the helical morphology is formed, the increase in bending energy together with the derivation from a perfect hexagonal mesostructure may limit the curvature of helices. Our model may be general and important in the designed synthesis of helical mesoporous materials.

Phototrigger‐controlled drug‐release devices (PDDs) can be conveniently manipulated by light to obtain on‐demand release patterns, thereby affording an improved therapeutic efficacy. However, no example of the PDDs has been demonstrated beyond the cellular level to date. By loading 7‐amino‐coumarin derivative caged anticancer drug chlorambucil to yolk–shell structured nanocages possessing upconversion nanophosphors (UCNPs) as moveable core and silica as mesoporous shell, a near‐infrared (NIR)‐regulated PDD is successfully created. In vitro experiments demonstrate that drug release from the PDD could be triggered by continuous‐wave 980 nm light in a controlled pattern. The PDD could be taken up by cancer cells and release the drug to kill cancer cells upon NIR irradiation. Further in vivo studies demonstrate that the PDD can effectively response the NIR stimuli in living tissue. This is the first example of successful NIR‐regulated drug release in living animal model. Such achievement resolves the problem of low tissue penetration depth for traditional PDDs by adopting UCNPs as an NIR light switcher, which gives impetus to practical applications.

The interstitial fluid (ISF) drainage pathway has been hypothesized to underlie the clearance of solutes and metabolites from the brain. Previous work has implicated the perivascular spaces along arteries as the likely route for ISF clearance, however it has never been demonstrated directly. The accumulation of amyloid β (Aβ) peptides in brain parenchyma is one of the pathological hallmarks of Alzheimer disease (AD), and it is likely related to an imbalance between production and clearance of the peptide. Aβ drainage along perivascular spaces has been postulated to be one of the mechanisms that mediates the peptide clearance from the brain. We therefore devised a novel method to visualize solute clearance in real time in the living mouse brain using laser guided bolus dye injections and multiphoton imaging. This methodology allows high spatial and temporal resolution and revealed the kinetics of ISF clearance. We found that the ISF drains along perivascular spaces of arteries and capillaries but not veins, and its clearance exhibits a bi-exponential profile. ISF drainage requires a functional vasculature, as solute clearance decreased when perfusion was impaired. In addition, reduced solute clearance was observed in transgenic mice with significant vascular amyloid deposition; we suggest the existence of a feed-forward mechanism, by which amyloid deposition promotes further amyloid deposition. This important finding provides a mechanistic link between cerebrovascular disease and Alzheimer disease and suggests that facilitation of Aβ clearance along the perivascular pathway should be considered as a new target for therapeutic approaches to AD and CAA.

In Alzheimer’s disease soluble amyloid beta (sAβ) causes synaptic dysfunction and neuronal loss. Receptors involved in clearance of sAβ are not known. Here we use shRNA screening and identify the scavenger receptor Scara1 as a receptor for sAβ expressed on myeloid cells. To determine the role of Scara1 in clearance of sAβ in vivo, we cross Scara1 null mice with PS1-APP mice, a mouse model of Alzheimer’s disease and generate PS1-APP- Scara1-deficient mice. Scara1 deficiency markedly accelerates Aβ accumulation leading to increased mortality. In contrast, pharmacological upregulation of Scara1 expression on mononuclear phagocytes increases Aβ clearance. This approach is a potential treatment strategy for Alzheimer’s disease.

The ApoE4 allele is associated with increased risk of small vessel disease, which is a cause of vascular cognitive impairment. Here, we report that mice with targeted replacement (TR) of the ApoE gene with human ApoE4 have reduced neocortical cerebral blood flow compared to ApoE3-TR mice, an effect due to reduced vascular density rather than slowing of microvascular red blood cell flow. Furthermore, homeostatic mechanisms matching local delivery of blood flow to brain activity are impaired in ApoE4-TR mice. In a model of cerebral hypoperfusion, these cerebrovascular alterations exacerbate damage to the white matter of the corpus callosum and worsen cognitive dysfunction. Using 3-photon microscopy we found that the increased white matter damage is linked to an enhanced reduction of microvascular flow resulting in local hypoxia. Such alterations may be responsible for the increased susceptibility to hypoxic-ischemic lesions in the subcortical white matter of individuals carrying the ApoE4 allele.

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