Water-repelling behavior of the 1-D hematite nano-network.

Hematite is an attractive material used as electron transport layer in perovskite-based solar cells. Being hydrophilic in nature it attracts moisture, which can be damaging for perovskite layers. Therefore, it is important to make hematite moisture repelling, which can be beneficial for applications in solar cells or for protecting iron surfaces from further rust formation. In this work, we demonstrate that the systematic irradiation of nanostructured hematite with low-energy argon ions (Ar+) at various ion fluences can change the surface wettability as well as promote the formation of junctions between nanorods. The nano-welded network of the irradiated hematite turns out to be hydrophobic. Using TRI3DYN simulations, ion-induced surface roughening, the presence of surface oxygen vacancies, and joining between adjacent nanorods are predicted. Furthermore, the water-repelling behavior of the irradiated nano-network is evaluated using density functional theory (DFT) simulations by determining the interaction of water molecules with the surface. The interconnected hematite nano-network also shows a notable improvement in electrical conductivity.

Computational design of novel MAX phase alloys as potential hydrogen storage media combining first principles and cluster expansion methods.

Finding a suitable material for hydrogen storage under ambient atmospheric conditions is challenging for material scientists and chemists. In this work, using a first principles based cluster expansion approach, the hydrogen storage capacity of the Ti2AC (A = Al, Ti, Cr, Mn, Fe, Co, Ni, Cu, and Zn) MAX phase and its alloys was studied. We found that hydrogen is energetically stable in Ti-A layers in which the tetrahedral site consisting of one A atom and three Ti atoms is energetically more favorable for hydrogen adsorption than other sites in the Ti-A layer. Ti2CuC has the highest hydrogen adsorption energy than other Ti2AC phases. We find that the 83.33% Cu doped Ti2AlxCu1-xC alloy structure is both energetically and dynamically stable and can store 3.66 wt% hydrogen under ambient atmospheric conditions, which is higher than that stored by both Ti2AlC and Ti2CuC phases. These findings indicate that the hydrogen capacity of the MAX phase can be significantly improved by doping an appropriate atom species.

A Steady-State Approach for Studying Valley Relaxation Using an Optical Vortex Beam.

Spin-valley coupling in monolayer transition-metal dichalcogenides gives rise to valley polarization and coherence effect, limited by intervalley scattering caused by exciton-phonon, exciton-impurity, and electron-hole exchange interactions (EHEIs). We explore an approach to tune the EHEI by controlling the exciton center of mass momentum (COM) utilizing the photon distribution of higher-order optical vortex beams. By virtue of this, we have observed exciton-COM-dependent valley depolarization and decoherence, which gives us the ability to probe the valley relaxation time scale in a steady-state measurement. Our steady-state technique to probe the valley dynamics can open up a new paradigm to explore the physics of excitons in two-dimensional systems.

Alteration of Wettability of Copper-Copper Oxide Nanocomposites through Cu-O Bond Breaking Swayed by Ultraviolet and Electron Irradiation.

Converting a nonwetting surface to a highly wetting one, aided by ultraviolet radiation, is well explored. Here, in this work, we show just the reverse behavior of a copper-copper oxide nanocomposite surface where ultraviolet radiation turned the superhydrophilic surface to a superhydrophobic one. This observation is explained both experimentally and theoretically using first-principles density functional theory-based calculations considering the metal-oxygen (Cu-O) bond breaking and related change in surface chemistry. This observation has further been corroborated with electron irradiation on the same nanocomposite material. To the best of our knowledge, for the first time, we show that the radiation-induced breaking of the copper-oxygen bond makes the nanostructure surface energetically unfavorable for water adsorption.

VEGF receptor-1 modulates amyloid ß 1-42 oligomer-induced senescence in brain endothelial cells.

Aggregated amyloid ß (Aß) peptides in the Alzheimer's disease (AD) brain are hypothesized to trigger several downstream pathologies, including cerebrovascular dysfunction. Previous studies have shown that Aß peptides can have antiangiogenic properties, which may contribute to vascular dysfunction in the early stages of the disease process. We have generated data showing that brain endothelial cells (ECs) exposed to toxic Aß1-42 oligomers can readily enter a senescence phenotype. To determine the effect of Aß oligomers on brain ECs, we treated early passaged human brain microvascular ECs and HUVECs with high MW Aß1-42 oligomers (5 µM, for 72 h). For controls, we used no peptide treatment, 5 µM Aß1-42 monomers, and 5 µM Aß1-42 fibrils, respectively. Brain ECs treated with Aß1-42 oligomers showed increased senescence-associated ß-galactosidase staining and increased senescence-associated p21/p53 expression. Treatment with either Aß1-42 monomer or Aß1-42 fibrils did not induce senescence in this assay. We then measured vascular endothelial growth factor receptor (VEGFR) expression in the Aß1-42 oligomer-treated ECs, and these cells showed significantly increased VEGFR-1 expression and decreased VEGFR-2 levels. Overexpression of VEGFR-1 in brain ECs readily induced senescence, suggesting a direct role of VEGFR-1 signaling events in this paradigm. More importantly, small interfering RNA-mediated knockdown of VEGFR-1 expression in brain ECs was able to prevent up-regulation of p21 protein expression and significantly reduced induction of senescence following Aß1-42 oligomer treatment. Our studies show that exposure to Aß1-42 oligomers may impair vascular functions by altering VEGFR-1 expression and causing ECs to enter a senescent phenotype. Altered VEGFR expression has been documented in brains of AD patients and suggests that this pathway may play a role in AD disease pathogenesis. These studies suggest that modulating VEGFR-1 expression and signaling events could potentially prevent senescence and rejuvenate EC functions, and provides us with a novel target to pursue for prevention and treatment of cerebrovascular dysfunction in AD.-Angom, R. S., Wang, Y., Wang, E., Pal, K., Bhattacharya, S., Watzlawik, J. O., Rosenberry, T. L., Das, P., Mukhopadhyay, D. VEGF receptor-1 modulates amyloid ß 1-42 oligomer-induced senescence in brain endothelial cells.

Nanoscale modification of one-dimensional single-crystalline cuprous oxide.

In this work we report for the first time a method to modify the surface of Cu2O nanowires in a controllable way and physically weld them into a network form, which contributes to higher electrical conductivity as well as a strong water-repelling nature. We have used state-of-the-art theoretical calculations to support our experimental observations. We demonstrate how varying the irradiation fluence can modulate the surface and decorate the nanowire with a uniform distribution of Cu8O nanocrystals due to preferential sputtering. While several well studied joining techniques are available for carbon and metal-based nanowires, the same information for ceramic nanowires is scarce at present. The current study sheds light into this and a state-of-the-art 3D simulation technique predicts most of the modifications including surface modulation, oxygen depletion and welding. The welded network shows higher electrical conductivity than the unwelded assembly. With Cu2O being of p-type the current ion beam joining technique shows a novel path for fabricating p-i-n junctions or solar cell devices through bottom-up approach. Furthermore, we have explored the response of this network to moisture. Our calculation based on density functional theory predicts the hydrophilic nature of individual copper oxide nanowires both before and after irradiation. However, the network shows a strong water-repelling nature, which has been explained quantitatively using the Cassie-Baxter model.

Combination of Aß Suppression and Innate Immune Activation in the Brain Significantly Attenuates Amyloid Plaque Deposition.

Anti-Aß clinical trials are currently under way to determine whether preventing amyloid deposition will be beneficial in arresting progression of Alzheimer disease. Both clinical and preclinical studies suggest that antiamyloid strategies are only effective if started at early stages of the disease process in a primary prevention strategy. Because this approach will be difficult to deploy, strategies for secondary prevention aimed at later stages of disease are also needed. In this study, we asked whether combining innate immune activation in the brain with concurrent Aß suppression could enhance plaque clearance and could improve pathologic outcomes in mice with moderate amyloid pathologic disorder. Starting at 5 months of age, tet-off amyloid precursor protein transgenic mice were treated with doxycycline (dox) to suppress further amyloid precursor protein/Aß production, and at the same time mice were intracranially injected with adeno-associated virus 1 expressing murine IL-6 (AAV1-mIL-6). Three months later, mice treated with the combination of Aß suppression and AAV1-mIL-6 showed significantly less plaque pathologic disorder than dox or AAV1-mIL-6 only groups. The combination of AAV1-mIL-6 + dox treatment lowered total plaque burden by >60% versus untreated controls. Treatment with either dox or AAV1-mIL-6 alone was less effective than the combination. Our results suggest a synergistic mechanism by which the up-regulation of mIL-6 was able to improve plaque clearance in the setting of Aß suppression.

Distinct spatiotemporal accumulation of N-truncated and full-length amyloid-ß42 in Alzheimer's disease.

Accumulation of amyloid-ß peptides is a dominant feature in the pathogenesis of Alzheimer's disease; however, it is not clear how individual amyloid-ß species accumulate and affect other neuropathological and clinical features in the disease. Thus, we compared the accumulation of N-terminally truncated amyloid-ß and full-length amyloid-ß, depending on disease stage as well as brain area, and determined how these amyloid-ß species respectively correlate with clinicopathological features of Alzheimer's disease. To this end, the amounts of amyloid-ß species and other proteins related to amyloid-ß metabolism or Alzheimer's disease were quantified by enzyme-linked immunosorbent assays (ELISA) or theoretically calculated in 12 brain regions, including neocortical, limbic and subcortical areas from Alzheimer's disease cases (n = 19), neurologically normal elderly without amyloid-ß accumulation (normal ageing, n = 13), and neurologically normal elderly with cortical amyloid-ß accumulation (pathological ageing, n = 15). We observed that N-terminally truncated amyloid-ß42 and full-length amyloid-ß42 accumulations distributed differently across disease stages and brain areas, while N-terminally truncated amyloid-ß40 and full-length amyloid-ß40 accumulation showed an almost identical distribution pattern. Cortical N-terminally truncated amyloid-ß42 accumulation was increased in Alzheimer's disease compared to pathological ageing, whereas cortical full-length amyloid-ß42 accumulation was comparable between Alzheimer's disease and pathological ageing. Moreover, N-terminally truncated amyloid-ß42 were more likely to accumulate more in specific brain areas, especially some limbic areas, while full-length amyloid-ß42 tended to accumulate more in several neocortical areas, including frontal cortices. Immunoprecipitation followed by mass spectrometry analysis showed that several N-terminally truncated amyloid-ß42 species, represented by pyroglutamylated amyloid-ß11-42, were enriched in these areas, consistent with ELISA results. N-terminally truncated amyloid-ß42 accumulation showed significant regional association with BACE1 and neprilysin, but not PSD95 that regionally associated with full-length amyloid-ß42 accumulation. Interestingly, accumulations of tau and to a greater extent apolipoprotein E (apoE, encoded by APOE) were more strongly correlated with N-terminally truncated amyloid-ß42 accumulation than those of other amyloid-ß species across brain areas and disease stages. Consistently, immunohistochemical staining and in vitro binding assays showed that apoE co-localized and bound more strongly with pyroglutamylated amyloid-ß11-x fibrils than full-length amyloid-ß fibrils. Retrospective review of clinical records showed that accumulation of N-terminally truncated amyloid-ß42 in cortical areas was associated with disease onset, duration and cognitive scores. Collectively, N-terminally truncated amyloid-ß42 species have spatiotemporal accumulation patterns distinct from full-length amyloid-ß42, likely due to different mechanisms governing their accumulations in the brain. These truncated amyloid-ß species could play critical roles in the disease by linking other clinicopathological features of Alzheimer's disease.

Morvan's syndrome-is a pathogen behind the curtain?

Morvan's syndrome is a rare syndrome of likely autoimmune etiology characterized by peripheral nerve hyperexcitability, dysautonomia, insomnia, and fluctuating delirium with prominent hallucinations. Since its first mention in 1890, less than 100 cases have been described in literature. The largest existing review includes details of 29 cases. This case series describes 4 cases (M = 4) of Morvan's syndrome which presented between May and November 2017 to a single tertiary care referral teaching hospital in north India. All the four patients manifested behavioral abnormalities, sleep disturbances, hallucinations, autonomic dysfunction, and clinical signs of peripheral nerve hyperexcitability, mostly as myokymia. Two of the patients had Anti-CASPR2 (contactin-associated protein 2) antibodies. Three of them had electromyography features of peripheral nerve hyperexcitability and only one had elevated cerebrospinal fluid protein level. We hypothesize that Morvan's syndrome and other less characterized autoimmune encephalitis/peripheral nervous system syndromes may have infectious triggers. A possible viral trigger may result in generation of autoantibodies which result in the typical manifestations. We base these hypotheses on the finding of four cases of an orphan disease within a short period of time in a limited geographical distribution.

Apolipoprotein E Is a Ligand for Triggering Receptor Expressed on Myeloid Cells 2 (TREM2).

Several heterozygous missense mutations in the triggering receptor expressed on myeloid cells 2 (TREM2) have recently been linked to risk for a number of neurological disorders including Alzheimer disease (AD), Parkinson disease, and frontotemporal dementia. These discoveries have re-ignited interest in the role of neuroinflammation in the pathogenesis of neurodegenerative diseases. TREM2 is highly expressed in microglia, the resident immune cells of the central nervous system. Along with its adaptor protein, DAP12, TREM2 regulates inflammatory cytokine release and phagocytosis of apoptotic neurons. Here, we report apolipoprotein E (apoE) as a novel ligand for TREM2. Using a biochemical assay, we demonstrated high-affinity binding of apoE to human TREM2. The functional significance of this binding was highlighted by increased phagocytosis of apoE-bound apoptotic N2a cells by primary microglia in a manner that depends on TREM2 expression. Moreover, when the AD-associated TREM2-R47H mutant was used in biochemical assays, apoE binding was vastly reduced. Our data demonstrate that apoE-TREM2 interaction in microglia plays critical roles in modulating phagocytosis of apoE-bound apoptotic neurons and establish a critical link between two proteins whose genes are strongly linked to the risk for AD.

Genetic suppression of transgenic APP rescues Hypersynchronous network activity in a mouse model of Alzeimer's disease.

Alzheimer's disease (AD) is associated with an elevated risk for seizures that may be fundamentally connected to cognitive dysfunction. Supporting this link, many mouse models for AD exhibit abnormal electroencephalogram (EEG) activity in addition to the expected neuropathology and cognitive deficits. Here, we used a controllable transgenic system to investigate how network changes develop and are maintained in a model characterized by amyloid ß (Aß) overproduction and progressive amyloid pathology. EEG recordings in tet-off mice overexpressing amyloid precursor protein (APP) from birth display frequent sharp wave discharges (SWDs). Unexpectedly, we found that withholding APP overexpression until adulthood substantially delayed the appearance of epileptiform activity. Together, these findings suggest that juvenile APP overexpression altered cortical development to favor synchronized firing. Regardless of the age at which EEG abnormalities appeared, the phenotype was dependent on continued APP overexpression and abated over several weeks once transgene expression was suppressed. Abnormal EEG discharges were independent of plaque load and could be extinguished without altering deposited amyloid. Selective reduction of Aß with a γ-secretase inhibitor has no effect on the frequency of SWDs, indicating that another APP fragment or the full-length protein was likely responsible for maintaining EEG abnormalities. Moreover, transgene suppression normalized the ratio of excitatory to inhibitory innervation in the cortex, whereas secretase inhibition did not. Our results suggest that APP overexpression, and not Aß overproduction, is responsible for EEG abnormalities in our transgenic mice and can be rescued independently of pathology.

Uncoupling of endothelial nitric oxide synthase in cerebral vasculature of Tg2576 mice.

In this study, we tested the hypothesis that reduced bioavailability of tetrahydrobiopterin (BH4) is a major mechanism responsible for pathogenesis of endothelial dysfunction in cerebral microvessels of transgenic mice expressing the Swedish double mutation of human amyloid precursor protein (APP) (Tg2576 mice). Endothelial nitric oxide synthase (eNOS) protein expression was significantly increased in cerebral vasculature of Tg2576 mice. In contrast, bioavailability of BH4 was significantly reduced (p < 0.05). Moreover, superoxide anion production was increased in cerebral microvessels of Tg2576 mice (p < 0.05). Incubation with NOS inhibitor, Nω-nitro-L-arginine methyl ester, decreased superoxide anion indicating that uncoupled eNOS is most likely the source of superoxide anion. Increasing BH4 bioavailability either exogenously by BH4 supplementation or endogenously by treatment with the selective peroxisome proliferator-activated receptor--delta activator GW501516 (2 mg/kg/day, 14 days) attenuated eNOS uncoupling and decreased superoxide anion production in cerebral microvessels of Tg2576 mice (p < 0.05). Treatment with GW501516 restored the biological activity of endothelial nitric oxide in cerebral microvessels of Tg2576 mice, as indicated by the increased nitrite/nitrate content and 3,5-cyclic guanosine monophosphate levels (p < 0.05). Our studies indicate that sub-optimal BH4 bioavailability in cerebral vasculature is an important contributor to oxidant stress and endothelial dysfunction in Tg2576 mouse model of Alzheimer's disease. Existing evidence suggests that Aß peptides-induced up-regulation of expression and activity of NADPH oxidase causes increased production of superoxide anion (.O2(-)). .O2(-) can also be converted to hydrogen peroxide (H2O2) by enzymatic activity of superoxide dismutase (SOD) or spontaneous dismutation. Elevation of .O2(-) and H2O2 might cause oxidation of tetrahydrobiopterin (BH4) to dihydrobiopterin (BH2) and subsequent uncoupling of endothelial nitric oxide synthase (eNOS) (a) thus reducing levels of nitric oxide (NO) and 3',5'-cyclic guanosine monophosphate (cGMP). Supplementation of BH4 or activation of PPARδ prevents detrimental effects of eNOS uncoupling by restoring bioavailability of BH4 and scavenging of .O2(-), respectively (b). Activation of PPARδ also increases expression of catalase thereby inactivating H2O2. Generation of H2O2 by uncoupled eNOS in cerebral microvessels of Tg2576 mice is hypothetical.

Regional distribution of synaptic markers and APP correlate with distinct clinicopathological features in sporadic and familial Alzheimer's disease.

Recent studies suggest that subcortical structures, including striatum, are vulnerable to amyloid-ß accumulation and other neuropathological features in familial Alzheimer's disease due to autosomal dominant mutations. We explored differences between familial and sporadic Alzheimer's disease that might shed light on their respective pathogenic mechanisms. To this end, we analysed 12 brain regions, including neocortical, limbic and subcortical areas, from post-mortem brains of familial Alzheimer's disease (n = 10; age at death: 50.0 ± 8.6 years) with mutations in amyloid precursor protein (APP) or presenilin 1 (PSEN1), sporadic Alzheimer's disease (n = 19; age at death: 84.7 ± 7.8 years), neurologically normal elderly without amyloid-ß accumulation (normal ageing; n = 13, age at death: 82.9 ± 10.8 years) and neurologically normal elderly with extensive cortical amyloid-ß deposits (pathological ageing; n = 15; age at death: 92.7 ± 5.9 years). The levels of amyloid-ß40, amyloid-ß42, APP, apolipoprotein E, the synaptic marker PSD95 (now known as DLG4), the astrocyte marker GFAP, other molecules related to amyloid-ß metabolism, and tau were determined by enzyme-linked immunosorbent assays. We observed that familial Alzheimer's disease had disproportionate amyloid-ß42 accumulation in subcortical areas compared with sporadic Alzheimer's disease, whereas sporadic Alzheimer's disease had disproportionate amyloid-ß42 accumulation in cortical areas compared to familial Alzheimer's disease. Compared with normal ageing, the levels of several proteins involved in amyloid-ß metabolism were significantly altered in both sporadic and familial Alzheimer's disease; however, such changes were not present in pathological ageing. Among molecules related to amyloid-ß metabolism, the regional distribution of PSD95 strongly correlated with the regional pattern of amyloid-ß42 accumulation in sporadic Alzheimer's disease and pathological ageing, whereas the regional distribution of APP as well as ß-C-terminal fragment of APP were strongly associated with the regional pattern of amyloid-ß42 accumulation in familial Alzheimer's disease. Apolipoprotein E and GFAP showed negative regional association with amyloid-ß (especially amyloid-ß40) accumulation in both sporadic and familial Alzheimer's disease. Familial Alzheimer's disease had greater striatal tau pathology than sporadic Alzheimer's disease. In a retrospective medical record review, atypical signs and symptoms were more frequent in familial Alzheimer's disease compared with sporadic Alzheimer's disease. These results suggest that disproportionate amyloid-ß42 accumulation in cortical areas in sporadic Alzheimer's disease may be mediated by synaptic processes, whereas disproportionate amyloid-ß42 accumulation in subcortical areas in familial Alzheimer's disease may be driven by APP and its processing. Region-specific amyloid-ß42 accumulation might account for differences in the relative amounts of tau pathology and clinical symptoms in familial and sporadic Alzheimer's disease.

Fabrication of Implant-Supported Auricular Prosthesis Using Artificial Intelligence.

The absence of any organ of the facial region causes an asymmetrical appearance. This asymmetrical appearance can cause social dilemmas for the patient. The maxillofacial technician, the prosthodontist, and the patient must work closely together to fabricate an epithesis. On the implants, a superstructure is first constructed. Most of it is made up of rings and a bar that joins the implants. The firm acrylic resin base of the epithesis is equipped with clips that serve as the epithesis's retention mechanism. The actual epithesis is made of silicone rubber. The epithesis has to be shaped and colored with extreme caution. An appropriate substitute is an auricular prosthesis that is implant-retained. Microtia, deformity, malformation, and loss of the external ear, either partially or completely, can result from a variety of inherited genetic conditions. To evaluate the symmetry of both ears, artificial intelligence (AI) software is used. An Instagram lens Gridset by crystalwavesxx was used to correct and verify the bilateral symmetry of the patient. This case report primarily focuses on the fabrication of implant-supported auricular prostheses using AI.

Changes in plasma concentrations of novel vascular and inflammatory biomarkers in obstructive sleep apnea patients pre- and post-stroke.

BACKGROUND: Obstructive sleep apnea (OSA) is increasingly recognized as a common condition in the general population and causes significant OSA-associated morbidities including cardiovascular and cerebrovascular events such as cerebral small vessel disease (CSVD) and stroke. METHODS: In this study, using sensitive ELISA immunoassays, we measured subset of endothelial/vascular and inflammatory biomarkers as well as neurofilament light chain (NfL), a sensitive marker for neuroaxonal injury, using plasma from OSA patients post-stroke (Acute Cerebral Infarction (ACI), N = 26) to determine their usefulness as potential prognostic markers in disease progression. RESULTS: Our results showed significantly increased plasma TNFα and NfL concentrations and decreased concentrations of platelet derived growth factor (PDGF-AA) in post-stroke OSA patients with more severe white matter hyperintensities (WMHs). And after separating the patients based on sex, compared to females, male post-stroke OSA patients with severe WMHs have increased circulating levels of inflammatory chemokine CXCL10 and cytokine Interleukin-10 (IL-10) and significantly decreased levels of Angiopoietin-1 (Ang-1) an important protein responsible for endothelial/vascular integrity functions. Importantly, in a subset of newly diagnosed OSA patients (without prior history of stroke), significantly increased plasma CXCL10 levels and decreased plasma Ang-1 levels were also readily observed when compared to healthy controls, indicating possible altered endothelial integrity and ongoing vascular inflammation in these newly diagnosed OSA patients. CONCLUSIONS: In summary, our study has identified a novel set of plasma biomarkers including PDGF-AA, CXCL10 and Ang-1 for their potential prognostic value for disease outcomes pre- and post-stroke in OSA patients and use as surrogate markers to measure efficacy of treatment modalities.

Portal Vein Reconstruction-trans Jugular Intrahepatic Portosystemic Shunt and Portal Vein Stenting in Patients With Extrahepatic Portal Vein Obstruction.

Extrahepatic portal vein thrombosis (EHPVO) is an uncommon cause of portal hypertension. In the long term, patients may develop portal cavernoma cholangiopathy (PCC). Up to 30%-40% of patients with EHPVO may not have shuntable veins and are often difficult to manage surgically. Interventional treatment including portal vein recanalisation-trans jugular intrahepatic portosystemic shunt (PVRecan-TIPS) has been used for patients with EHPVO. However, PV reconstruction-trans jugular intrahepatic portosystemic shunt (PVRecon-TIPS) and portal vein stenting are novel techniques for managing such patients with EHPVO with non-shuntable venous anatomy. In contrast to PVRecan-TIPS, PV reconstruction-TIPS (PVRecon-TIPS) is performed through intrahepatic collaterals. Here we present six cases of PCC who presented with recurrent acute variceal bleeding (AVB) and or refractory biliary stricture. They did not have any shuntable veins. PVRecon-TIPS was performed for five patients whilst PV stenting was done in one. Amongst the six patients, one died of sepsis whilst one who developed hyponatremia and hepatic encephalopathy was salvaged with conservative management. Following the procedure, they were started on anti-coagulation. Decompression of cavernoma was documented in all other patients. Biliary changes improved completely in 40% of patients.

Robust amyloid clearance in a mouse model of Alzheimer's disease provides novel insights into the mechanism of amyloid-beta immunotherapy.

Many new therapeutics for Alzheimer's disease delay the accumulation of amyloid-ß (Aß) in transgenic mice, but evidence for clearance of preexisting plaques is often lacking. Here, we demonstrate that anti-Aß immunotherapy combined with suppression of Aß synthesis allows significant removal of antecedent deposits. We treated amyloid-bearing tet-off APP (amyloid precursor protein) mice with doxycycline to suppress transgenic Aß production before initiating a 12 week course of passive immunization. Animals remained on doxycycline for 3 months afterward to assess whether improvements attained during combined treatment could be maintained by monotherapy. This strategy reduced amyloid load by 52% and Aß42 content by 28% relative to pretreatment levels, with preferential clearance of small deposits and diffuse Aß surrounding fibrillar cores. We demonstrate that peripherally administered anti-Aß antibody crossed the blood-brain barrier, bound to plaques, and was still be found associated with a subset of amyloid deposits many months after the final injection. Antibody accessed the brain independent of plasma Aß levels, where it enhanced microglial internalization of aggregated Aß. Our data support a mechanism by which passive immunization acts centrally to stimulate microglial phagocytosis of aggregated Aß, but is opposed by the continued aggregation of newly secreted Aß. By arresting the production of Aß, combination therapy allows microglial clearance to work from a static amyloid burden toward a significant reduction in plaque load. Our findings suggest that combining two therapeutic approaches currently in clinical trials may improve neuropathological outcome over either alone.

Lysine 624 of the amyloid precursor protein (APP) is a critical determinant of amyloid ß peptide length: support for a sequential model of γ-secretase intramembrane proteolysis and regulation by the amyloid ß precursor protein (APP) juxtamembrane region.

γ-Secretase is a multiprotein intramembrane cleaving aspartyl protease (I-CLiP) that catalyzes the final cleavage of the amyloid ß precursor protein (APP) to release the amyloid ß peptide (Aß). Aß is the primary component of senile plaques in Alzheimer's disease (AD), and its mechanism of production has been studied intensely. γ-Secretase executes multiple cleavages within the transmembrane domain of APP, with cleavages producing Aß and the APP intracellular domain (AICD), referred to as γ and ε, respectively. The heterogeneous nature of the γ cleavage that produces various Aß peptides is highly relevant to AD, as increased production of Aß 1-42 is genetically and biochemically linked to the development of AD. We have identified an amino acid in the juxtamembrane region of APP, lysine 624, on the basis of APP695 numbering (position 28 relative to Aß) that plays a critical role in determining the final length of Aß peptides released by γ-secretase. Mutation of this lysine to alanine (K28A) shifts the primary site of γ-secretase cleavage from 1-40 to 1-33 without significant changes to ε cleavage. These results further support a model where ε cleavage occurs first, followed by sequential proteolysis of the remaining transmembrane fragment, but extend these observations by demonstrating that charged residues at the luminal boundary of the APP transmembrane domain limit processivity of γ-secretase.

IFN-gamma promotes complement expression and attenuates amyloid plaque deposition in amyloid beta precursor protein transgenic mice.

Reactive gliosis surrounding amyloid beta (Abeta) plaques is an early feature of Alzheimer's disease pathogenesis and has been postulated to represent activation of the innate immune system in an apparently ineffective attempt to clear or neutralize Abeta aggregates. To evaluate the role of IFN-gamma-mediated neuroinflammation on the evolution of Abeta pathology in transgenic (Tg) mice, we have expressed murine IFN-gamma (mIFN-gamma) in the brains of Abeta precursor protein (APP) Tg mice using recombinant adeno-associated virus serotype 1. Expression of mIFN-gamma in brains of APP TgCRND8 mice results in robust noncell autonomous activation of microglia and astrocytes, and a concomitant significant suppression of Abeta deposition. In these mice, mIFN-gamma expression upregulated multiple glial activation markers, early components of the complement cascade as well as led to infiltration of Ly-6c positive peripheral monocytes but no significant effects on APP levels, APP processing or steady-state Abeta levels were noticed in vivo. Taken together, these results suggest that mIFN-gamma expression in the brain suppresses Abeta accumulation through synergistic effects of activated glia and components of the innate immune system that enhance Abeta aggregate phagocytosis.