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Background: Alzheimer's disease (AD) is an age-related disease characterized by altered cognition, neuroinflammation, and neurodegeneration against which there is presently no effective cure. Brain-derived neurotrophic factor (BDNF) is a key neurotrophin involved in the learning and memory process, with a crucial role in synaptic plasticity and neuronal survival. Several findings support that a reduced BDNF expression in the human brain is associated with AD pathogenesis. BDNF has been proposed as a potential therapy for AD, but BDNF has low brain penetration. In this study, we used an innovative encapsulated cell biodelivery (ECB) device, containing genetically modified cells capable of releasing BDNF and characterized its feasibility and therapeutic effects in the novel App knock-in AD mouse model (AppNL−G−F). Methods: ECB's containing human ARPE-19 cells genetically modified to release BDNF (ECB-BDNF devices) were stereotactically implanted bilaterally into hippocampus of 3-month-old AppNL−G−F mice. The stability of BDNF release and its effect on AD pathology were evaluated after 1, 2-, and 4-months post-implantation by immunohistochemical and biochemical analyses. Exploratory and memory performance using elevated plus maze (EPM) and Y-maze test were performed in the 4-months treatment group. Immunological reaction towards ECB-BDNF devices were studied under ex vivo and in vivo settings. Results: The surgery and the ECB-BDNF implants were well tolerated without any signs of unwanted side effects or weight loss. ECB-BDNF devices did not induce host-mediated immune response under ex vivo set-up but showed reduced immune cell attachment when explanted 4-months post-implantation. Elevated BDNF staining around ECB-BDNF device proximity was detected after 1, 2, and 4 months treatment, but the retrieved devices showed variable BDNF release. A reduction of amyloid-β (Aβ) plaque deposition was observed around ECB-BDNF device proximity after 2-months of BDNF delivery. Conclusions: The result of this study supports the use of ECB device as a promising drug-delivery approach to locally administer BBB-impermeable factors for treating neurodegenerative conditions like AD. Optimization of the mouse-sized devices to reduce variability of BDNF release is needed to employ the ECB platform in future pre-clinical research and therapy development studies. [ABSTRACT FROM AUTHOR]

The amyloid [beta]-peptide (A[beta]) has been suggested to exert its toxicity intracellularly. Mitochondrial functions can be negatively affected by A[beta] and accumulation of A[beta] has been detected in mitochondria. Because A[beta] is not likely to be produced locally in mitochondria, we decided to investigate the mechanisms for mitochondrial A[beta] uptake. Our results from rat mitochondria show that A[beta] is transported into mitochondria via the translocase of the outer membrane (TOM) machinery. The import was insensitive to valinomycin, indicating that it is independent of the mitochondrial membrane potential. Subfractionation studies following the import experiments revealed A[beta] association with the inner membrane fraction, and immunoelectron microscopy after import showed localization of A[beta] to mitochondrial cristae. A similar distribution pattern of A[beta] in mitochondria was shown by immunoelectron microscopy in human cortical brain biopsies obtained from living subjects with normal pressure hydrocephalus. Thus, we present a unique import mechanism for A[beta] in mitochondria and demonstrate both in vitro and in vivo that A[beta] is located to the mitochondrial cristae. Importantly, we also show that extracellulary applied A[beta] can be internalized by human neuroblastoma cells and can colocalize with mitochondrial markers. Together, these results provide further insight into the mitochondrial uptake of A[beta], a peptide considered to be of major significance in Alzheimer's disease. Alzheimer disease | protein import | human brain biopsies

The role of inflammation in HIV transmission in investigated by studying the infectious and inflammatory milieu in cervical mucosa from HIV-1- and human papillomavirus (HPV)-coinfected and HPV-monoinfected women. The results have indicated the persistence of immune activation and inflammation in the genital tract of women with HPV monoinfection and in HIV-infected women coinfected with HPV.

Highly active antiretroviral therapy (HAART) may restore immune activity in lymph tissue, according to a study of 3 HIV patients. Although HAART suppressed virus in the blood, some cells in the tonsils still contained virus for up to one year after treatment began.

Background: Dementia disorders affect millions of people worldwide, among which Alzheimer's disease (AD) accounts for 60% cases. Treatment of these disorders are constrained due to inefficient brain availability of peripherally administered drugs. Conversely, direct intracerebroventricular injections are counterintuitive due to unspecific side‐effects. Recently, Aducanumab has shown potential to clear amyloid plaques from AD brain, but its efficacy to revive clinical symptoms are under debate. In this regard, direct delivery of regenerative biological drugs utilizing encapsulated cell biodelivery (ECB) has gained much attention. Conversely, how the pathological microenvironment of the AD brain affects these encapsulated drug‐delivering cells are scarcely understood. The ECB approach nullifies immune reaction from host tissue by protecting drug‐delivering cells from direct physical contact with the host tissue. Thus, in this study we probe the effect of factors released from activated human microglial cells (HMC3 cell line) on ECB devices harboring nerve growth factor (NGF) releasing cells (NGC0211; modified human ARPE‐19 cells). Method: ECB devices harboring NGC0211 cells were manufactured and maintained in DMEM/F12 culture medium containing 10% serum until used. HMC3 cells were activated using AD related molecules including 1µM amyloid beta (Aβ40 and Aβ42) peptides and 10ng/mL inflammatory cytokines (interferon‐γ, IFN‐γ; interleukin‐1β, IL‐1β; or both) for 24hrs, and a cell free microglia conditioned medium (MCM) was obtained. ECB devices were then exposed to various MCMs, and NGF release was followed for several weeks assessed by ELISA (DY256, R&D systems). Similarly, non‐encapsulated NGC0211 cells grown in multi‐well slides were exposed to MCMs and cellular proliferation (Ki67 expression) along with senescence parameters (SA‐β‐galactosidase) were evaluated. Result: We found that factors released from activated microglia hampered NGF release from ECB devices. Simultaneously, MCMs reduced Ki67 expression and elevated SA‐β‐galactosidase activity in NGC0211 cells. Conclusion: Activated microglia, a common feature of all neurodegenerative conditions, impair NGF release, cellular proliferation and induce senescence in NGC0211 cells. Similar impact of microglia on other types of drug‐delivering cells (stem cells or genetically modified) needs to be studied. Our study highlights one of the probable underlying causes for impaired long‐term cell mediated drug delivery in neurodegenerative diseases and helps guide improvements in the technologies. [ABSTRACT FROM AUTHOR]

Abstract: Cerebral autosomal‐dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a familial fatal progressive degenerative disorder. One of the pathological hallmarks of CADASIL is a dramatic reduction of vascular smooth muscle cells (VSMCs) in cerebral arteries. Using VSMCs from the vasculature of the human umbilical cord, placenta and cerebrum of CADASIL patients, we found that CADASIL VSMCs had a lower proliferation rate compared to control VSMCs. Exposure of control VSMCs and endothelial cells (ECs) to media derived from CADASIL VSMCs lowered the proliferation rate of all cells examined. By quantitative RT‐PCR analysis, we observed increased Transforming growth factor‐β (TGFβ) gene expression in CADASIL VSMCs. Adding TGFβ‐neutralizing antibody restored the proliferation rate of CADASIL VSMCs. We assessed proliferation differences in the presence or absence of TGFβ‐neutralizing antibody in ECs co‐cultured with VSMCs. ECs co‐cultured with CADASIL VSMCs exhibited a lower proliferation rate than those co‐cultured with control VSMCs, and neutralization of TGFβ normalized the proliferation rate of ECs co‐cultured with CADASIL VSMCs. We suggest that increased TGFβ expression in CADASIL VSMCs is involved in the reduced VSMC proliferation in CADASIL and may play a role in situ in altered proliferation of neighbouring cells in the vasculature. [ABSTRACT FROM AUTHOR]

Background: Alzheimer's disease (AD) is an age‐related disease characterized by synaptic dysfunction, brain inflammation, and neurodegeneration against which there is no effective cure available. Brain‐Derived Neurotrophic Factor (BDNF) is a key molecule involved in the learning and memory process, with a crucial role in synaptic plasticity and neuronal survival. Several findings support that a reduced BDNF expression in the human brain is associated with AD pathogenesis. BDNF has been proposed as a potential therapy for AD, but BDNF has low brain permeability. In this study, we used an innovative encapsulated cell biodelivery (ECB) device containing cells capable of locally delivering BDNF to characterize its neuroprotective effects in the novel AD APP‐knock‐in mouse model AppNL‐G‐F. Method: ECB devices with human ARPE‐19 cells modified to release BDNF were surgically bilaterally implanted in the hippocampus of 3‐month‐old AppNL‐G‐F mice. BDNF effects on AD pathology were evaluated after 1, 2, and 3 months of treatment by immunohistochemical and biochemical analysis. In the 3‐month‐treated groups, exploratory and memory performances were also evaluated using Elevated Plus Maze (EPM) and Y‐maze tests. Result: The ECB implants were well tolerated with no signs of unwanted side effects or weight loss. A high BDNF staining was detected in most of the brains in the area surrounding the devices at 1‐3 months, but retrieved devices showed variability of BDNF release. Interestingly, three months of BDNF treatment significantly improved AppNL‐G‐F mice´s anxiety behavior in EPM and improved the spontaneous behavioral alternations in the Y‐maze test. Conclusion: The results of this study are encouraging and support the BDNF device as a promising approach for treating cognitive AD decline. Optimization of the mouse‐sized devices to reduce the variability of BDNF release is needed for future experiments and translated to larger devices for clinical translation. [ABSTRACT FROM AUTHOR]