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Background: Signal Peptide Peptidase‐Like 2b (SPPL2b) is relevant for AD, being a brain‐specific intramembrane protein involved in the cleavage of Alzheimer's disease (AD)‐related proteins, such as BRI2, inflammatory‐related proteins like CD74, TNFalpha, and Clec7a, and synaptic proteins Neuregulin‐1 and VAMP 1‐4. SPPL2b is specifically expressed in the hippocampus and cortex. The cleavage of TNFalpha by SPPL2b promotes the inflammatory pathway. Conversely, the SPPL2b substrate BRI2 regulates amyloid precursor protein (APP) cleavage and subsequent Aβ production. This work explores the pathophysiological role of SPPL2b in AD pathogenesis and investigates the potential of inhibiting SPPL2b activity as a novel therapeutic strategy. Method: To characterize the role of SPPL2b in the APP cleavage process and neuroinflammation, we used neurons and glia primary cell cultures from WT and SPPL2b‐deficient mice. Furthermore, we assessed the therapeutic potential of inhibiting SPPL2b by employing a new AD mouse model generated through crossbreeding state‐of‐the‐art AppNL‐G‐F knock‐in mice with SPPL2b‐deficient mice. Cells and mouse brain samples were analyzed through western blotting, immunoprecipitation, and immunofluorescence. Aβ levels were quantified using ELISA kits. Result: The results showed a significant increase in BRI2, followed by a substantial reduction in soluble APP, Aβ40, and Aβ42 levels in the conditioned media of SPPL2b KO neurons. Immunoprecipitation of BRI2 from the cortex of those mice revealed an increased interaction between BRI2 and APP in SPPL2b KO/AppNL‐G‐F mice. Most importantly, a notable decrease in brain Aβ plaque deposition and a significant decrease in both cortical and hippocampal gliosis were observed at 4 months‐of‐age in SPPL2b KO/AppNL‐G‐F mice. Conclusion: The results outlined in this study support a relevant connection between SPPL2b and the development of Aβ pathology in AD. In a global scenario characterized by the need to identify novel strategies to prevent and counteract AD progression, this study highlights and strengthens the importance of SPPL2b as a novel therapeutic approach for AD. [ABSTRACT FROM AUTHOR]

Background: High age is the biggest risk factor for Alzheimer's disease (AD). Approved drugs that slow down the aging process have the potential to be repurposed for the primary prevention of AD. The aim of our project was to use a reverse translational approach to identify such drug candidates in epidemiological data followed by validation in cell‐based models and animal models of aging and AD. Method: Longitudinal samples from a Swedish twin cohort (N = 672) were used to assess the effects of commonly prescribed medications on biological aging. Mendelian Randomization was used to identify associations between genetic variations in the glucagon‐like peptide 1 (GLP‐1) analogues target and the risk of developing AD. The identified classes of compounds were next evaluated in a pipe line of cellular and animal models for their potency of increasing lifespan using C. elegans models expressing amyloidbeta (Aβ) and tau, and for lowering Aβ levels in neuroblastoma SH‐SY5Y cells and AD‐associated pathologies in AppNL‐F knock‐in mice as well as their anti‐aging effects in a novel mouse model of CNS aging. Result: We found that initiation of calcium channel blockers (CCBs) was associated with about a two‐year decrease in multiple epigenetic clocks (DNA methylation ages) as well as in functional biological ages. Moreover, genetic variants in GLP‐1 targets were associated with lower risk of developing AD. Several of the clinically used CCBs significantly increased the life span in C. elegans Aβ model and decreased levels of secreted Aβ from SH‐SY5Y cells. Several GLP‐1 analogues, similar to the CCBs, demonstrated a positive effect in reducing Aβ42 levels in SH‐SY5Y cell media. Conclusion: These preliminary data, demonstrating an extension of lifespan and a reduction in Aβ42 production, support the potential repurposing strategy for CCBs and GLP‐1 analogs in slowing down aging and preventing/treating AD. The investigation of these compounds in mouse models of aging and AD will provide a more complete picture of the therapeutic potential and may eventually identify novel preventive measures for AD within CCB and GLP‐1 analogs. [ABSTRACT FROM AUTHOR]

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]

Simple Summary: Alzheimer's disease (AD) is a complex, multifactorial disease where numerous components, such as environment, lifestyle, comorbidities, and genetic predisposition, contribute to triggering the onset of the disease. Several neurobiological brain alterations have been reported during AD pathologies, including the endocannabinoid system (ECS) and associated lipid transmitter-based signaling systems. In this study, we have evaluated the expression levels of the cannabinoid receptors type 2 (CB2) and the novel cannabinoid/lysophospholipid G protein-coupled receptor 55 (GPR55) at different stages of AD. We deeply investigated CB2 and GPR55's close proximity with Aβ-plaque deposits, as well as neuronal and glial cells, in the AD AppNL-G-F knock-in mouse model. Additionally, we analyzed whether Aβ42 directly affects CB2 and GPR55 protein expression in neuronal and glial primary cell cultures. Our study shows that the ECS, specifically the CB2 and GPR55 receptors, are altered during AD pathology. Monitoring these receptors may provide new biomarkers for AD diagnosis. CB2 and GPR55 could be potential pharmacological targets for selective compounds to treat AD inflammation. Background: The endocannabinoid system (ECS) and associated lipid transmitter-based signaling systems play an important role in modulating brain neuroinflammation. ECS is affected in neurodegenerative disorders, such as Alzheimer's disease (AD). Here we have evaluated the non-psychotropic endocannabinoid receptor type 2 (CB2) and lysophosphatidylinositol G-protein-coupled receptor 55 (GPR55) localization and expression during Aβ-pathology progression. Methods: Hippocampal gene expression of CB2 and GPR55 was explored by qPCR analysis, and brain distribution was evaluated by immunofluorescence in the wild type (WT) and APP knock-in AppNL-G-F AD mouse model. Furthermore, the effects of Aβ42 on CB2 and GPR55 expression were assessed in primary cell cultures. Results: CB2 and GPR55 mRNA levels were significantly upregulated in AppNL-G-F mice at 6 and 12 months of age, compared to WT. CB2 was highly expressed in the microglia and astrocytes surrounding the Aβ plaques. Differently, GPR55 staining was mainly detected in neurons and microglia but not in astrocytes. In vitro, Aβ42 treatment enhanced CB2 receptor expression mainly in astrocytes and microglia cells, whereas GPR55 expression was enhanced primarily in neurons. Conclusions: These data show that Aβ pathology progression, particularly Aβ42, plays a crucial role in increasing the expression of CB2 and GPR55 receptors, supporting CB2 and GPR55 implications in AD. [ABSTRACT FROM AUTHOR]

Background: Increasing epidemiological, clinical, and experimental evidence suggests that Alzheimer's disease (AD) pathogenesis is closely associated with systemic abnormalities, including dynamic processes in the peripheral immune compartment and inflammation1,2,3. Recent reports in transgenic AD animal models propose a role of dysregulated peripheral immune system in memory impairment4,5. In this regard, the contribution of peripheral immune response in driving different pathological stages in AD is less understood. Therefore, utilizing a novel App knock‐in mouse model (AppNL‐G‐F) exhibiting robust Aβ pathology, neuroinflammation and memory impairment, we have explored the relation of Aβ pathology development in the brain with alterations in the peripheral immune compartment. Method: Using flowcytometry, we characterized the AppNL‐G‐F mice at different stages of Aβ pathology (early‐plaque: 3‐month‐old; plaque + early memory impairment: 7‐month‐old; late stages: 12‐month‐old) and investigated the distribution and activation status of various peripheral immune cells in splenic primary cells. Result: Among various immune cells from innate immunity including macrophages, natural killer and dendritic cells, there was a significant increase in macrophage number in AppNL‐G‐F mice. While percent distribution of B cells from adaptive immunity was reduced (as observed in AD patients2), no significant changes in total T cell distribution following 3, 7 and 12‐months of age compared to wild‐type controls was observed. B cells showed reduced activation examined by CD69 and PD‐L1 expression in 7 and 12‐months old AppNL‐G‐F mice. Among T cell subsets, CD4, CD8 and regulatory T (Treg) cell distribution in AppNL‐G‐F mice was comparable to control mice in all age groups. However, there was rise in follicular T helper (Tfh) cells at 3‐month of age, with altered activation molecule ICOS expression in AppNL‐G‐Fmice. Conclusion: These findings in AD mice model show a reduction in B cell and their activation status during aggressive Aβ plaque deposition in brain, reflecting their possible contribution in Aβ pathology reinforcing the importance of further investigation. Our data suggest a possible role of Tfh cell in early stage of Aβ pathology. An altered Tfh cell activation may answer the impaired protective antibody production from B cells reported in AD6,7. The observed increase in macrophages in the peripheral system during Aβ pathology development demands further investigation. [ABSTRACT FROM AUTHOR]