IL‐1β/IL‐1R1 signaling induced by intranasal lipopolysaccharide infusion regulates alpha‐Synuclein pathology in the olfactory bulb,substantia nigra and striatum

Olfactory dysfunction is one of the early symptoms seen in Parkinson’s disease (PD). However, the mechanisms underlying olfactory pathology that impacts PD disease progression and post‐mortem appearance of alpha‐Synuclein (α‐Syn) inclusions in and beyond olfactory bulb in PD remain unclear. It has been suggested that environmental toxins inhaled through the nose can induce inflammation in the olfactory bulb (OB), where Lewy body (LB) is the first to be found, and then, spread to related brain regions. We hypothesize that OB inflammation triggers local α‐Syn pathology and promotes its spreading to cause PD. In this study, we evaluated this hypothesis by intranasal infusion of lipopolysaccharides (LPS) to induce OB inflammation in mice and examined cytokines expression and PD‐like pathology. We found intranasal LPS‐induced microglia activation, inflammatory cytokine expression and α‐Syn overexpression and aggregation in the OB via interleukin‐1β (IL‐1β)/IL‐1 receptor type I (IL‐1R1) dependent signaling. In addition, an aberrant form of α‐Syn, the phosphorylated serine 129 α‐Syn (pS129 α‐Syn), was found in the OB, substantia nigra (SN) and striatum 6 weeks after the LPS treatment. Moreover, 6 weeks after the LPS treatment, mice showed reduced SN tyrosine hydroxylase, decreased striatal dopaminergic metabolites and PD‐like behaviors. These changes were blunted in IL‐1R1 deficient mice. Further studies found the LPS treatment inhibited IL‐1R1‐dependent autophagy in the OB. These results suggest that IL‐1β/IL‐1R1 signaling in OB play a vital role in the induction and propagation of aberrant α‐Syn, which may ultimately trigger PD pathology.     

TRDMT1 exhibited protective effects against LPS‐induced inflammation in rats through TLR4‐NF‐κB/MAPK‐TNF‐α pathway

BackgroundInflammation is a complex physiological and pathological process. Although many types of inflammation are well characterized, their physiological functions are largely unknown. tRNA aspartic acid methyltransferase 1 (TRDMT1) has been implicated as a stress‐related protein, but its intrinsic biological role is unclear.MethodsWe constructed a Trdmt1 knockout rat and adopted the LPS‐induced sepsis model. Survival curve, histopathological examination, expression of inflammatory factors, and protein level of TLR4 pathway were analyzed.Results Trdmt1 deletion had no obvious impact on development and growth. Trdmt1 deletion slightly increased the mortality during aging. Our data showed that Trdmt1 strongly responded in LPS‐treated rats, and Trdmt1 knockout rats were vulnerable to LPS treatment with declined survival rate. We also observed more aggravated tissue damage and more cumulative functional cell degeneration in LPS‐treated knockout rats compared with control rats. Further studies showed upregulated TNF‐α level in liver, spleen, lung, and serum tissues, which may be explained by enhanced p65 and p38 phosphorylation.ConclusionsOur data demonstrated that Trdmt1 plays a protective role in inflammation by regulating the TLR4‐NF‐κB/MAPK‐TNF‐α pathway. This work provides useful information to understand the TRDMT1 function in inflammation.     

Cytokine TGF-β1, TNF-α, IFN-γ and IL‐6 Gene Polymorphisms and Localization of Premalignant Gastric Lesions in Immunohistochemically H. pylori-negative Patients

Background: Cytokines and their gene variants are proven to play a role in pathogenic gastritis and carcinogenesis. The study assesses associations of the cytokine gene polymorphisms with extension of atrophic gastritis/intestinal metaplasia (AGIM) in patients without Helicobacter pylori infection on immunohistochemistry study.Methods: 224 adult consecutive patients undergoing an upper digestive endoscopy were included and grouped according to localization of AGIM: 37 patients with antrum-limited AGIM, 21 corpus-limited AGIM, 15 extended-AGIM (antrum and corpus) and 151 patients had no AGIM. Medical records of the patients were checked and a structured direct interview was applied in order to collect clinical data, including digestive symptoms. In all cases, IFN-γ +874T>A, TGF-β1 +869T>C, TNF‐α-308G>A and -238G>A, and IL-6 -174C>G polymorphisms were genotyped.Results: The mean age was significantly higher in the AGIM group, while the comorbidies were similar among patients with different localization of lesions or in patients without AGIM. There were no significant differences in digestive symptoms, nor in the consumption of non-steroidal anti-inflammatory drugs or proton pump inhibitor with the different extensions of AGIM. There was a significant association between oral anticoagulant consumption and localization of AGIM (P = 0.042), frequency being higher among patients with corpus-limited AGIM than those with no AGIM (P = 0.007, adjusted P = 0.041). TGF-β1 +869T>C was less frequent among patients with corpus-limited AGIM (n=7, 33.3%) and extended AGIM (n=5, 33.3%) than in antrum-limited AGIM (n=25, 67.6%). There were no other significant differences regarding variant and wild genotype frequencies of IFN-γ +874T>A (86.5%, 81.0%, 86.7%, p=0.814), TNF‐α-308G>A (35.1%, 28.6%, 53.3%, p=0.48) and IL-6 -174C>G (70.3%. 61.9%, 73.3% p=0.656) among patients with antrum-limited, corpus-limited or extended AGIM. TGF-β1 +869T>C was associated with a decreased risk for corpus-affected AGIM (adjusted odds ratio: 0.42, 95% confidence interval: 0.19-0.93, P = 0.032). The dominant inheritance models no revealed significant association for IFN-γ +874T>A, TNF‐α-308G>A and IL-6 -174C>G gene polymorphism and the risk of localization of AGIM.Conclusion: TGF-β1 +869T>C gene polymorphism is associated with a decreased risk for corporeal localization of premalignant lesions, while IFN-γ +874T>A, TNF-α-308G>A and IL-6 -174C>G are not associated with the risk for AGIM in immunohistochemically H. pylori negative patients.     

Role of miR‐21‐5p/FilGAP axis in estradiol alleviating the progression of monocrotaline‐induced pulmonary hypertension

BackgroundAberrant expression of microRNAs (miRNAs) has been associated with the pathogenesis of pulmonary hypertension (PH). It is, however, not clear whether miRNAs are involved in estrogen rescue of PH.MethodsFresh plasma samples were prepared from 12 idiopathic pulmonary arterial hypertension (IPAH) patients and 12 healthy controls undergoing right heart catheterization in Shanghai Pulmonary Hospital. From each sample, 5 μg of total RNA was tagged and hybridized on microRNA microarray chips. Monocrotaline‐induced PH (MCT‐PH) male rats were treated with 17β‐estradiol (E₂) or vehicle. Subgroups were cotreated with estrogen receptor (ER) antagonist or with antagonist of miRNA.ResultsMany circulating miRNAs, including miR‐21‐5p and miR‐574‐5p, were markedly expressed in patients and of interest in predicting mean pulmonary arterial pressure elevation in patients. The expression of miR‐21‐5p in the lungs was significantly upregulated in MCT‐PH rats compared with the controls. However, miR‐574‐5p showed no difference in the lungs of MCT‐PH rats and controls. miR‐21‐5p was selected for further analysis in rats as E₂ strongly regulated it. E₂ decreased miR‐21‐5p expression in the lungs of MCT‐PH rats by ERβ. E₂ reversed miR‐21‐5p target gene FilGAP downregulation in the lungs of MCT‐PH rats. The abnormal expression of RhoA, ROCK2, Rac1 and c‐Jun in the lungs of MCT‐PH rats was inhibited by E₂ and miR‐21‐5p antagonist.ConclusionsmiR‐21‐5p level was remarkably associated with PH severity in patients. Moreover, the miR‐21‐5p/FilGAP signaling pathway modulated the protective effect of E₂ on MCT‐PH through ERβ.     

Distinct Aβ pathology in the olfactory bulb and olfactory deficits in a mouse model of Aβ and α‐syn co‐pathology

Several degenerative brain disorders such as Alzheimer''s disease (AD), Parkinson''s disease (PD) and Dementia with Lewy bodies (DLB) are characterized by the simultaneous appearance of amyloid‐β (Aβ) and α‐synuclein (α‐syn) pathologies and symptoms that are similar, making it difficult to differentiate between these diseases. Until now, an accurate diagnosis can only be made by postmortem analysis. Furthermore, the role of α‐syn in Aβ aggregation and the arising characteristic olfactory impairments observed during the progression of these diseases is still not well understood. Therefore, we assessed Aβ load in olfactory bulbs of APP‐transgenic mice expressing APP695 ^KM670/671NL and PSEN1 ^L166P under the control of the neuron‐specific Thy‐1 promoter (referred to here as APPPS1) and APPPS1 mice co‐expressing SNCA ^A30P (referred to here as APPPS1 × [A30P]aSYN). Furthermore, the olfactory capacity of these mice was evaluated in the buried food and olfactory avoidance test. Our results demonstrate an age‐dependent increase in Aβ load in the olfactory bulb of APP‐transgenic mice that go along with exacerbated olfactory performance. Our study provides clear evidence that the presence of α‐syn significantly diminished the endogenous and seed‐induced Aβ deposits and significantly ameliorated olfactory dysfunction in APPPS1 × [A30P]aSYN mice.     

Changes with Age in the Activities of β‐Secretase and the Aβ‐Degrading Enzymes Neprilysin,Insulin‐Degrading Enzyme and Angiotensin‐Converting Enzyme

We recently found that insoluble Aβ increases, but soluble Aβ decreases with age in normal brains. We now report the changes in activities of β‐secretase (BACE‐1) and Aβ‐degrading enzymes with age, and their relationships to concentrations of soluble and insoluble Aβ. We measured BACE‐1 activity and the levels and activities of neprilysin (NEP), insulin‐degrading enzyme (IDE) and angiotensin‐converting enzyme (ACE) in normal control brains (16 years–95 years). We also compared the measurements to those in AD. BACE‐1 activity correlated closely with age in controls and was significantly higher in AD. In controls, NEP and IDE activities (but not protein levels) increased with age but ACE activity and level did not. BACE‐1 activity correlated directly with insoluble but inversely with soluble Aβ. IDE activity correlated directly with insoluble Aβ and NEP activity was inversely related to soluble Aβ. ACE level correlated directly with insoluble and inversely with soluble Aβ in controls but not AD. Both Aβ‐synthesizing and ‐degrading enzyme activities increase with age, coinciding with declining soluble Aβ and increasing insoluble Aβ. Further research is needed to establish whether these changes in enzyme activity and Aβ levels are causally related and if so how.     

Knockdown of HIF‐1α impairs post‐ischemic vascular reconstruction in the brain via deficient homing and sprouting bmEPCs

Although the critical role of hypoxia inducible factor‐1α (HIF‐1α) in cerebral neovascularization after stroke has been well characterized, the details regarding the regulation of endothelial progenitor cell (EPC)‐dependent neovascularization by HIF‐1α are not completely understood. Using lentiviral shRNA to knockdown HIF‐1α, we showed that HIF‐1α plays a central role in bone marrow‐derived EPC (bmEPC) homing and sprouting in the post‐acute stage of ischemic Sprague Dawley (SD) rat brains. First, knockdown of HIF‐1α decreased the homing of both endogenous and exogenous bmEPCs to the ischemic brain. Additionally, the knockdown impaired the incorporation and sprouting of bmEPCs in the ischemic brain. In vitro, knockdown of HIF‐1α inhibited the spheroid sprouting and tube formation of bmEPCs. Mechanically, the HIF‐1α‐dependent recruitment of bmEPCs to the ischemic brain was relative to the CXCL12/CXCR4 axis and HMGB1, which were relative to astrocytes. In addition, the loss of HIF‐1α resulted in deficient expression levels of VEGF‐A, Flk‐1, NRP1, and Dll4 in the ischemic brains, bmEPCs, and astrocytes. These findings suggested that HIF‐1α implicates in bmEPC homing via CXCL12/CXCR4 and HMGB1 and that it promotes bmEPC sprouting via VEGF‐A/flk1‐NRP1/Dll4.     

Temporal overexpression of IL‐22 and Reg3γ differentially impacts the severity of experimental autoimmune encephalomyelitis

IL‐22 is an alpha‐helical cytokine which belongs to the IL‐10 family of cytokines. IL‐22 is produced by RORγt+ innate and adaptive lymphocytes, including ILC3, γδ T, iNKT, Th17 and Th22 cells and some granulocytes. IL‐22 receptor is expressed primarily by non‐haematopoietic cells. IL‐22 is critical for barrier immunity at the mucosal surfaces in the steady state and during infection. Although IL‐22 knockout mice were previously shown to develop experimental autoimmune encephalomyelitis (EAE), a murine model of multiple sclerosis (MS), how temporal IL‐22 manipulation in adult mice would affect EAE course has not been studied previously. In this study, we overexpressed IL‐22 via hydrodynamic gene delivery or blocked it via neutralizing antibodies in C57BL/6 mice to explore the therapeutic impact of IL‐22 modulation on the EAE course. IL‐22 overexpression significantly decreased EAE scores and demyelination, and reduced infiltration of IFN‐γ+IL‐17A+Th17 cells into the central nervous system (CNS). The neutralization of IL‐22 did not alter the EAE pathology significantly. We show that IL‐22‐mediated protection is independent of Reg3γ, an epithelial cell‐derived antimicrobial peptide induced by IL‐22. Thus, overexpression of Reg3γ significantly exacerbated EAE scores, demyelination and infiltration of IFN‐γ+IL‐17A+ and IL‐17A+GM‐CSF+Th17 cells to CNS. We also show that Reg3γ may inhibit IL‐2‐mediated STAT5 signalling and impair expansion of Treg cells in vivo and in vitro. Finally, Reg3γ overexpression dramatically impacted intestinal microbiota during EAE. Our results provide novel insight into the role of IL‐22 and IL‐22‐induced antimicrobial peptide Reg3γ in the pathogenesis of CNS inflammation in a murine model of MS.     

Progression of phosphorylated α‐synuclein in Macaca fuscata

Prion‐like spreading of abnormal proteins is proposed to occur in neurodegenerative diseases, and the progression of α‐synuclein (α‐syn) deposits has been reported in the brains of animal models injected with synthetic α‐syn fibrils or pathological α‐syn prepared from patients with Parkinson''s disease (PD) and dementia with Lewy bodies (DLB). However, α‐syn transmission in nonhuman primates, which are more similar to humans, has not been fully clarified. Here, we injected synthetic human α‐syn fibrils into the left striatum of a macaque monkey (Macaca fuscata). At 3 months after the injection, we examined neurodegeneration and α‐syn pathology in the brain using α‐syn epitope‐specific antibodies, antiphosphorylated α‐syn antibodies (pSyn#64 and pSer129), anti‐ubiquitin antibodies, and anti‐p62 antibodies. Immunohistochemical examination with pSyn#64, pSer129, and α‐syn epitope‐specific antibodies revealed Lewy bodies, massive α‐syn‐positive neuronal intracytoplasmic inclusions (NCIs), and neurites in the left putamen. These inclusions were also positive for ubiquitin and p62. LB509, a human‐specific α‐syn antibody targeting amino acid residues 115–122, showed limited immunoreactivity around the injection site. The left substantia nigra (SN) and the bilateral frontal cortex also contained some NCIs and neurites. The left hemisphere, including parietal/temporal cortex presented sparse α‐syn pathology, and no immunoreactivity was seen in olfactory nerves, amygdala, hippocampus, or right parietal/temporal cortex. Neuronal loss and gliosis in regions with α‐syn pathology were mild, except for the left striatum and SN. Our results indicate that abnormal α‐syn fibrils propagate throughout the brain of M. fuscata via projection, association, and commissural fibers, though the progression of α‐syn pathology is limited.     

Aitongxiao improves pain symptoms of rats with cancer pain by reducing IL-1, TNF-α, and PGE2

Objective: To explore the mechanism of Aitongxiao in improving pain symptoms of rats with cancer pain. Methods: Walker 256 breast cancer cells were injected into the right tibial bone marrow cavity of normal female rats to establish a rat model of tibial cancer pain. The rats with successful model replication were randomly divided into normal group (NG), Hank solution group (HSG), cancer pain model group (CPMG), and Aitongxiao+cancer pain model group (ATX+CPMG). The pain response score, mechanical pain hindpaw withdrawal threshold, and latent heat pain of rats were evaluated, and the changes of serum IL-1β, TNF-α, PGE2 and blood cell counts of rats were detected. Results: Compared with the NG, the pain response score was increased, the mechanical pain hindpaw withdrawal threshold and latent heat pain were decreased, and IL-1β, TNF-α, and PGE2 were increased in CPMG. Compared with the CPMG, the pain response score was decreased, the mechanical pain hindpaw withdrawal threshold and latent heat pain were increased, and IL-1β, TNF-α, and PGE2 were decreased in ATX+CPMG. There was no significant change in blood cell count in each group. Conclusion: Aitongxiao can improve the pain symptoms of rats with tibial cancer pain. Its mechanism may be related to the reduction of IL-1β, TNF-α, and PGE2 levels.     

Impact of α‐synuclein spreading on the nigrostriatal dopaminergic pathway depends on the onset of the pathology

Misfolded α‐synuclein spreads along anatomically connected areas through the brain, prompting progressive neurodegeneration of the nigrostriatal pathway in Parkinson''s disease. To investigate the impact of early stage seeding and spreading of misfolded α‐synuclein along with the nigrostriatal pathway, we studied the pathophysiologic effect induced by a single acute α‐synuclein preformed fibrils (PFFs) inoculation into the midbrain. Further, to model the progressive vulnerability that characterizes the dopamine (DA) neuron life span, we used two cohorts of mice with different ages: 2‐month‐old (young) and 5‐month‐old (adult) mice. Two months after α‐synuclein PFFs injection, we found that striatal DA release decreased exclusively in adult mice. Adult DA neurons showed an increased level of pathology spreading along with the nigrostriatal pathway accompanied with a lower volume of α‐synuclein deposition in the midbrain, impaired neurotransmission, rigid DA terminal composition, and less microglial reactivity compared with young neurons. Notably, preserved DA release and increased microglial coverage in the PFFs‐seeded hemisphere coexist with decreased large‐sized terminal density in young DA neurons. This suggests the presence of a targeted pruning mechanism that limits the detrimental effect of α‐synuclein early spreading. This study suggests that the impact of the pathophysiology caused by misfolded α‐synuclein spreading along the nigrostriatal pathway depends on the age of the DA network, reducing striatal DA release specifically in adult mice.     

Role of VAPB and vesicular profiles in α‐synuclein aggregates in multiple system atrophy

The pathological hallmark of multiple system atrophy (MSA) is fibrillary aggregates of α‐synuclein (α‐Syn) in the cytoplasm and nucleus of both oligodendrocytes and neurons. In neurons, α‐Syn localizes to the cytosolic and membrane compartments, including the synaptic vesicles, mitochondria, and endoplasmic reticulum (ER). α‐Syn binds to vesicle‐associated membrane protein‐binding protein B (VAPB) in the ER membrane. Overexpression of wild‐type and familial Parkinson''s disease mutant α‐Syn perturbs the association between the ER and mitochondria, leading to ER stress and ultimately neurodegeneration. We examined brains from MSA patients (n = 7) and control subjects (n = 5) using immunohistochemistry and immunoelectron microscopy with antibodies against VAPB and phosphorylated α‐Syn. In controls, the cytoplasm of neurons and glial cells was positive for VAPB, whereas in MSA lesions VAPB immunoreactivity was decreased. The proportion of VAPB‐negative neurons in the pontine nucleus was significantly higher in MSA (13.6%) than in controls (0.6%). The incidence of cytoplasmic inclusions in VAPB‐negative neurons was significantly higher (42.2%) than that in VAPB‐positive neurons (3.6%); 67.2% of inclusion‐bearing oligodendrocytes and 51.1% of inclusion‐containing neurons were negative for VAPB. Immunoelectron microscopy revealed that α‐Syn and VAPB were localized to granulofilamentous structures in the cytoplasm of oligodendrocytes and neurons. Many vesicular structures labeled with anti‐α‐Syn were also observed within the granulofilamentous structures in the cytoplasm and nucleus of both oligodendrocytes and neurons. These findings suggest that, in MSA, reduction of VAPB is involved in the disease process and that vesicular structures are associated with inclusion formation.     

Wnt signaling pathway participates in valproic acid-induced neuronal differentiation of neural stem cells

Neural stem cells (NSCs) are multipotent cells that have the capacity for differentiation into the major cell types of the nervous system, i.e. neurons, astrocytes and oligodendrocytes. Valproic acid (VPA) is a widely prescribed drug for seizures and bipolar disorder in clinic. Previously, a number of researches have been shown that VPA has differential effects on growth, proliferation and differentiation in many types of cells. However, whether VPA can induce NSCs from embryonic cerebral cortex differentiate into neurons and its possible molecular mechanism is also not clear. Wnt signaling is implicated in the control of cell growth and differentiation during CNS development in animal model, but its action at the cellular level has been poorly understood. In this experiment, we examined neuronal differentiation of NSCs induced by VPA culture media using vitro immunochemistry assay. The neuronal differentiation of NSCs was examined after treated with 0.75 mM VPA for three, seven and ten days. RT-PCR assay was employed to examine the level of Wnt-3α and β-catenin. The results indicated that there were more β-tublin III positive cells in NSCs treated with VPA medium compared to the control group. The expression of Wnt-3α and β-catenin in NSCs treated with VPA medium was significantly greater compared to that of control media. In conclusion, these findings indicated that VPA could induce neuronal differentiation of NSCs by activating Wnt signal pathway.     

Neutralizing peripheral circulating IL1β slows the progression of ALS in a lentivirus‐infected OPTNE478G mouse model

BackgroundAmyotrophic lateral sclerosis (ALS) is irreversible and fatal within 3–5 years, with limited options for treatment. It is imperative to develop a symptom‐based treatment that may increase the survival of ALS patients and improve their quality of life. Inflammation status, especially elevated interleukin 1β (IL1β), has been reported to play a critical role in ALS progression. Our study determined that neutralizing circulating IL1β slows down the progression of ALS in an ALS mouse model.MethodsThe ALS mouse model was developed by microinjection of lentivirus‐carrying OPTN^E478G (optineurin, a mutation from ALS patients) into the intra‐motor cortex of mice. Peripheral circulating IL1β was neutralized by injecting anti‐IL1β antibody into the tail vein. Enzyme‐linked immunosorbent assay (ELISA) and real‐time polymerase chain reaction (RT‐PCR) were carried out to determine the protein and gene expression levels of IL1β. TUNEL assay was used to assess the neural cell death. Immunofluorescent staining of MAP2 and CASP3 was accomplished to evaluate neuronal cell apoptosis. Glial fibrillary acidic protein staining was performed to analyze the number of astrocytes. Rotarod test, grip strength test, balance beam test, and footprint test were conducted to assess the locomotive function after anti‐IL1β treatment.ResultsThe model revealed that neuroinflammation contributes to ALS progression. ALS mice exhibited elevated neuroinflammation and IL1β secretion. After anti‐IL1β treatment, ALS mice revealed decreased neural cell death and astrogliosis and gained improved muscle strength and motor ability.ConclusionsBlocking IL1β is a promising strategy to slow down the progression of ALS.     

Cellular response to β‐amyloid neurotoxicity in Alzheimer's disease and implications in new therapeutics

β‐Amyloid (Aβ) is a specific pathological hallmark of Alzheimer''s disease (AD). Because of its neurotoxicity, AD patients exhibit multiple brain dysfunctions. Disease‐modifying therapy (DMT) is the central concept in the development of AD therapeutics today, and most DMT drugs that are currently in clinical trials are anti‐Aβ drugs, such as aducanumab and lecanemab. Therefore, understanding Aβ''s neurotoxic mechanism is crucial for Aβ‐targeted drug development. Despite its total length of only a few dozen amino acids, Aβ is incredibly diverse. In addition to the well‐known Aβ_1‐42, N‐terminally truncated, glutaminyl cyclase (QC) catalyzed, and pyroglutamate‐modified Aβ (pEAβ) is also highly amyloidogenic and far more cytotoxic. The extracellular monomeric Aβ_x‐42 (x = 1–11) initiates the aggregation to form fibrils and plaques and causes many abnormal cellular responses through cell membrane receptors and receptor‐coupled signal pathways. These signal cascades further influence many cellular metabolism‐related processes, such as gene expression, cell cycle, and cell fate, and ultimately cause severe neural cell damage. However, endogenous cellular anti‐Aβ defense processes always accompany the Aβ‐induced microenvironment alterations. Aβ‐cleaving endopeptidases, Aβ‐degrading ubiquitin‐proteasome system (UPS), and Aβ‐engulfing glial cell immune responses are all essential self‐defense mechanisms that we can leverage to develop new drugs. This review discusses some of the most recent advances in understanding Aβ‐centric AD mechanisms and suggests prospects for promising anti‐Aβ strategies.     

Higher levels of kallikrein‐8 in female brain may increase the risk for Alzheimer's disease

Women seem to have a higher vulnerability to Alzheimer''s disease (AD), but the underlying mechanisms of this sex dichotomy are not well understood. Here, we first determined the influence of sex on various aspects of Alzheimer''s pathology in transgenic CRND8 mice. We demonstrate that beta‐amyloid (Aβ) plaque burden starts to be more severe around P180 (moderate disease stage) in female transgenics when compared to males and that aging aggravates this sex‐specific difference. Furthermore, we show that female transgenics suffer from higher levels of neurovascular dysfunction around P180, resulting in impaired Aβ peptide clearance across the blood‐brain‐barrier at P360. Female transgenics show also higher levels of diffuse microgliosis and inflammation, but the density of microglial cells surrounding Aβ plaques is less in females. In line with this finding, testosterone compared to estradiol was able to improve microglial viability and Aβ clearance in vitro. The spatial memory of transgenics was in general poorer than in wildtypes and at P360 worse in females irrespective of their genotype. This difference was accompanied by a slightly diminished dendritic complexity in females. While all the above‐named sex‐differences emerged after the onset of Aβ pathology, kallikrein‐8 (KLK8) protease levels were, as an exception, higher in female than in male brains very early when virtually no plaques were detectable. In a second step, we quantified cerebral KLK8 levels in AD patients and healthy controls, and could ascertain, similar to mice, higher KLK8 levels not only in AD‐affected but also in healthy brains of women. Accordingly, we could demonstrate that estradiol but not testosterone induces KLK8 synthesis in neuronal and microglial cells. In conclusion, multiple features of AD are more pronounced in females. Here, we show for the first time that this sex‐specific difference may be meditated by estrogen‐induced KLK8 overproduction long before AD pathology emerges.     

Synapsin III is a key component of α‐synuclein fibrils in Lewy bodies of PD brains

Lewy bodies (LB) and Lewy neurites (LN), which are primarily composed of α‐synuclein (α‐syn), are neuropathological hallmarks of Parkinson''s disease (PD) and dementia with Lewy bodies (DLB). We recently found that the neuronal phosphoprotein synapsin III (syn III) controls dopamine release via cooperation with α‐syn and modulates α‐syn aggregation. Here, we observed that LB and LN, in the substantia nigra of PD patients and hippocampus of one subject with DLB, displayed a marked immunopositivity for syn III. The in situ proximity ligation assay revealed the accumulation of numerous proteinase K‐resistant neuropathological inclusions that contained both α‐syn and syn III in tight association in the brain of affected subjects. Most strikingly, syn III was identified as a component of α‐syn‐positive fibrils in LB‐enriched protein extracts from PD brains. Finally, a positive correlation between syn III and α‐syn levels was detected in the caudate putamen of PD subjects. Collectively, these findings indicate that syn III is a crucial α‐syn interactant and a key component of LB fibrils in the brain of patients affected by PD.