Extracellular Amyloid Deposits Research Articles

POS-212 RENAL AA AMYLOIDOSIS: A RETROSPECTIVE CLINICOPATHOLOGIC STUDY WITH EMPHASIS ON PROGNOSIS CONDUCTED IN 74 FRENCH PATIENTS DIAGNOSED BETWEEN 2010 AND 2021

AA amyloidosis is a protein folding disease characterized by extracellular deposition of amyloid A fibrils derived from the serum amyloid A inflammation protein, causing kidney dysfunction in patients with chronic inflammatory conditions. Several histological studies found a link between the topography or abundance of amyloid deposits and clinical presentation or renal prognosis. However, most of these studies are now outdated, present a non-exhaustive clinical collection and may no longer represent the current epidemiology, especially in France.

From barnyard to bedside: using interspecies variants to inform the rational design of novel analogs of islet amyloid polypeptide

Islet amyloid polypeptide (IAPP, also known as amylin) is a 37-residue, neuropancreatic hormone that is co-secreted with insulin by islet β-cells and plays an important role in glycemic control. The peptide is linked to diabetes mellitus, forming extracellular amyloid deposits in type 2 disease and largely absent in type 1 disease. IAPP is found in all vertebrates and the sequence is well conserved, but some variants exhibit decreased in vitro amyloidogenicity and enhanced solubility in formulation.

Eyes on amyloidosis: microvascular retinal dysfunction in cardiac amyloidosis

AimsCardiac involvement in systemic amyloidosis is a marker of particularly poor prognosis. Cardiac amyloidosis (CA) is characterized by extracellular amyloid deposits inducing heart failure and symptoms of cardiac microvascular disease. While amyloid deposition is most common in the myocardium but also seen in pericardium and endocardium, atria, and vasculature, the role of (micro‐)vascular dysfunction in CA pathophysiology remains still elusive. Because vascular function is associated with cardiovascular risk and severity of heart failure and represents a potential therapeutic target in CA, the present study investigated retinal vascular function, flow‐mediated dilatation (FMD), and pulse‐wave analysis and velocity (PWA/PWV) in patients with CA.Methods and resultsFlicker‐induced arterial dilatation (FIDa) was measured using dynamic retinal vessel analysis additionally to FMD and PWA/PWV. Thirty‐three patients with CA [age 67 years [interquartile range, IQR, 62, 74], 14 with amyloid light‐chain (AL) and 19 with transthyretin (ATTR) amyloidosis] were prospectively included in this cross‐sectional, observational study and 70 healthy individuals (age 53 years [IQR 39, 67]) served as control. Potential confounders were balanced using entropy balancing propensity score analysis [inverse probability weighting (IPW)]. FIDa was reduced in CA patients (1.52 ± 1.73% vs. 3.09 ± 1.96%, P < 0.001, after IPW). While PWV was increased (8.74 ± 2.34 m/s vs. 7.49 ± 1.65 m/s, P = 0.018, after IPW), no difference in FMD was observed. FIDa was significantly associated with prognostic biomarkers of CA [estimated glomerular filtration rate (r = 0.33; P < 0.001), log‐scaled troponin T (r = −0.49; P < 0.001), and N‐terminal pro‐B‐type natriuretic peptide (r = −0.51; P < 0.001)].ConclusionsRetinal vascular function is impaired, associated with cardiac and renal biomarkers of CA severity, and may represent a potential therapeutic target in patients with amyloidosis.

Localized gastric amyloidosis successfully treated with endoscopic submucosal dissection

Rationale:Amyloidosis is a general term that refers to the extracellular deposition of amyloid. The amyloid can also be deposited in a single organ. However, cases of localized gastric amyloidosis have rarely been reported. Here, we report a case of localized gastric amyloidosis that was successfully treated with endoscopic submucosal dissection.Patient concern:A 60-years-old man underwent esophagogastroduodenoscopy as part of a regular check-up without any comorbidities or symptoms.Diagnostics:A 12 mm-sized, round, elevated lesion with a central depression, which was covered with normal mucosa, and located on the greater curvature of the lower body of the stomach was discovered during endoscopy. Subsequently, endoscopic ultrasonography was performed, which revealed a 11.7 mm-sized, hypoechoic, heterogeneous lesion located in the muscularis mucosa and submucosa. A biopsy was performed, and amyloid deposition was confirmed. Although other investigations for checking systemic amyloidosis were performed, there were no specific findings. Therefore, the final diagnosis was localized gastric amyloidosis.Interventions:Endoscopic submucosal dissection was performed according to the patient's request and the lesion was completely removed.Outcomes:The patient was followed-up for 3 years without any recurrence.Conclusions:Endoscopic submucosal dissection can be good diagnostic and treatment option for localized gastric amyloidosis.

C19. Cardiac Amyloidosis: A Great Pretender of Left Ventricular Hypertrophy with Systemic Manifestation

Abstract Background Systemic amyloidosis encompasses an underdiagnosed disorder characterized by the extracellular deposition of amyloid in one or more organs, including the heart. The therapeutic strategy depends on the characterization of amyloid protein type and the extent of the disease. When founding a pathological left ventricular hypertrophy, initial clues provided by electrocardiography and echocardiography combined with other clinical manifestations could support a suspicion of cardiac amyloidosis. Case Summary A 54-year-old male patient was repeatedly admitted to a local hospital for recurrent heart failure and refractory bilateral pleural effusions of unknown cause. There was intolerance of any heart failure medications and repeated thoracocentesis failed to control the pleural effusion. The echocardiogram revealed severely impaired left ventricular function with phenotypic overlap between hypertrophic and restrictive cardiomyopathy. In contrast, we found a low voltage electrocardiogram. After an extensive diagnostic workup, including speckle tracking echocardiography, cardiac magnetic resonance, serum immunofixation and free light chain, bone marrow biopsy, and also Congo Red staining for amyloid, the final diagnosis was light chain (AL) amyloidosis. Discussion Cardiac involvement in systemic amyloidosis is the leading cause of morbidity and mortality. Frequently, myocardial wall thickening is incorrectly referred to as hypertrophy which may potentially lead to the wrong diagnosis and therapy. However, a need remains for improved awareness and expertise, while a multidisciplinary approach is important in making the correct diagnosis and management of this debilitating disease.

C19. Cardiac Amyloidosis: A Great Pretender of Left Ventricular Hypertrophy with Systemic Manifestation

Abstract Background Systemic amyloidosis encompasses an underdiagnosed disorder characterized by the extracellular deposition of amyloid in one or more organs, including the heart. The therapeutic strategy depends on the characterization of amyloid protein type and the extent of the disease. When founding a pathological left ventricular hypertrophy, initial clues provided by electrocardiography and echocardiography combined with other clinical manifestations could support a suspicion of cardiac amyloidosis. Case Summary A 54-year-old male patient was repeatedly admitted to a local hospital for recurrent heart failure and refractory bilateral pleural effusions of unknown cause. There was intolerance of any heart failure medications and repeated thoracocentesis failed to control the pleural effusion. The echocardiogram revealed severely impaired left ventricular function with phenotypic overlap between hypertrophic and restrictive cardiomyopathy. In contrast, we found a low voltage electrocardiogram. After an extensive diagnostic workup, including speckle tracking echocardiography, cardiac magnetic resonance, serum immunofixation and free light chain, bone marrow biopsy, and also Congo Red staining for amyloid, the final diagnosis was light chain (AL) amyloidosis. Discussion Cardiac involvement in systemic amyloidosis is the leading cause of morbidity and mortality. Frequently, myocardial wall thickening is incorrectly referred to as hypertrophy which may potentially lead to the wrong diagnosis and therapy. However, a need remains for improved awareness and expertise, while a multidisciplinary approach is important in making the correct diagnosis and management of this debilitating disease.

S2749 A Rare Cause of Liver Cirrhosis and Gastritis: Primary Gastrointestinal Amyloidosis in a Patient With Multiple Myeloma

Introduction: The most common form, systemic amyloidosis, is characterized by production of amyloidogenic precursor proteins at a site, remote from the organs of amyloid deposition. Case Description/Methods: A 65-year old male with a 25 year history of chronic alcoholism, presented to the emergency department for a 2 week history of non-radiating right upper quadrant abdominal pain associated with pruritus, nausea, coffee ground emesis, and clay colored stools. The exam was notable for icteric sclera, right upper quadrant abdominal tenderness, ascites, and hepatomegaly. Initial work up revealed new onset unexplained elevated liver enzyme. Abdominal Ultrasound was significant for hepatomegaly with perihepatic ascites. The CT scan revealed diffuse liver cirrhosis, periportal lymphadenopathy, and stigmata of portal hypertension including hepatosplenomegaly, intra-abdominal ascites, and varices. Esophagogastroduodenoscopy with endoscopic ultrasound was performed, which showed gastritis, and enlarged porta hepatis, which was ultimately biopsied and sent for cytology and pathology. Given the unexplained elevation of the liver enzymes, and liver biopsy revealed extracellular amyloid deposition in peri-sinusoidal spaces consistent with amyloidosis. Transesophageal echocardiogram which raised suspicion for cardiac involvement with amyloid deposit. Immunoglobulin levels were subsequently investigated and showed elevated IgG antibodies. A K/L free ratio was elevated to 94.7. A myeloma flow cytometry exhibited an IgG kappa monoclonal-gammopathy. Finally, a CT-guided bone marrow biopsy from the iliac crest was obtained, confirming an IgG kappa multiple myeloma with 80% proportion of plasma cells (DS 2A, ISS 3). The patient was started on steroids, and chemotherapy with daratumumab, however his condition was complicated by septic shock, which led to an admission in the ICU followed by endotracheal intubation and multi-organ failure and eventual palliative care. Discussion: Localized GI and hepatic amyloidosis have rarely been described in the literature. This condition poses great diagnostic challenges and warrants extensive work up before definitive diagnosis. Our case highlights the importance of clinical suspicion of GI amyloidosis in patients with constitutional symptoms including fatigue, weight loss, and unexplained liver disease. Once amyloidosis is considered, the diagnosis can be obtained by tissue biopsy from either the GI tract or subcutaneous adipose tissue.Figure 1.: CT scan (A-B) showing hepatosplenomegaly, and peri-splenic varices (arrowheads). Pathologic findings (C-G) of AL type amyloidosis of the luminal gastrointestinal tract. C. Histologic examination (Hematoxylin-Eosin staining) of a gastric antral type mucosa with chronic inactive gastritis and interstitial deposition of pink amorphous material (white asterisk). Histologic examination of liver with amorphous material deposition: Hematoxylin-Eosin staining (black asterisk in D-E), and crystal violet staining (G). F. Vascular wall are almost always involved first in the systemic amyloidosis (Hematoxylin-Eosin staining).

Extracellular amyloid deposition in sporadic inclusion body myositis: Further insights

See article on pages 590–594 in this issue

Interstitial amyloidosis in sporadic inclusion body myositis.

Intracellular congophilic inclusions within muscle fibers, although nonspecific, are one of the pathological hallmarks of sporadic inclusion body myositis (sIBM). Extracellular amyloid deposits in muscle, on the other hand, are the canonical findings of amyloid myopathies, which occur with or without systemic amyloidosis. We reviewed the muscle biopsy database (1998-2020) to identify sIBM patients with extracellular amyloid deposits. Clinical and laboratory data were reviewed. We identified five sIBM patients (three clinicopathologically defined and two clinically defined) with extracellular amyloid deposits in muscle. Mean age at diagnosis was 74.8y (range, 68-84 y). All patients had a typical sIBM pattern of weakness without associated sensory or autonomic symptoms. None had electrophysiological evidence of peripheral neuropathy. Only one patient had a monoclonal gammopathy (immunoglobulin M-lambda, IgM-λ) with normal bone marrow biopsy. This patient with monoclonal gammopathy and three other patients underwent abdominal fat pad aspirate and were negative for amyloid. Cardiac evaluation was unrevealing in the four patients tested. Three patients without monoclonal gammopathy had normal transthyretin gene sequencing and inconclusive mass spectrometry-based analysis. The patient with monoclonal gammopathy died of pneumosepsis 5y after diagnosis and autopsy revealed multi-organ transthyretin amyloidosis. Detection of extracellular amyloid deposition in muscle should trigger an aggressive search for systemic amyloidosis independently from other associated myopathological abnormalities. Amyloid subtyping is crucial for early therapy and mortality prevention. An isolated monoclonal gammopathy should not halt a search for non-hematological causes of systemic amyloidosis.

Structure of Tau filaments in Prion protein amyloidoses

In human neurodegenerative diseases associated with the intracellular aggregation of Tau protein, the ordered cores of Tau filaments adopt distinct folds. Here, we analyze Tau filaments isolated from the brain of individuals affected by Prion-Protein cerebral amyloid angiopathy (PrP-CAA) with a nonsense mutation in the PRNP gene that leads to early termination of translation of PrP (Q160Ter or Q160X), and Gerstmann–Sträussler–Scheinker (GSS) disease, with a missense mutation in the PRNP gene that leads to an amino acid substitution at residue 198 (F198S) of PrP. The clinical and neuropathologic phenotypes associated with these two mutations in PRNP are different; however, the neuropathologic analyses of these two genetic variants have consistently shown the presence of numerous neurofibrillary tangles (NFTs) made of filamentous Tau aggregates in neurons. We report that Tau filaments in PrP-CAA (Q160X) and GSS (F198S) are composed of 3-repeat and 4-repeat Tau isoforms, having a striking similarity to NFTs in Alzheimer disease (AD). In PrP-CAA (Q160X), Tau filaments are made of both paired helical filaments (PHFs) and straight filaments (SFs), while in GSS (F198S), only PHFs were found. Mass spectrometry analyses of Tau filaments extracted from PrP-CAA (Q160X) and GSS (F198S) brains show the presence of post-translational modifications that are comparable to those seen in Tau aggregates from AD. Cryo-EM analysis reveals that the atomic models of the Tau filaments obtained from PrP-CAA (Q160X) and GSS (F198S) are identical to those of the Tau filaments from AD, and are therefore distinct from those of Pick disease, chronic traumatic encephalopathy, and corticobasal degeneration. Our data support the hypothesis that in the presence of extracellular amyloid deposits and regardless of the primary amino acid sequence of the amyloid protein, similar molecular mechanisms are at play in the formation of identical Tau filaments.

Endoscopic submucosal dissection for localized amyloidosis of the sigmoid colon.

Amyloidosis is a rare disease caused by the extracellular deposition of amyloid, which results from the self-assembly of various precursor proteins with a highly ordered and abnormal cross-β sheet structure [1] [2].

The Role of Sphingolipids and Specialized Pro-Resolving Mediators in Alzheimer's Disease.

Alzheimer’s disease (AD) is the leading cause of dementia worldwide giving rise to devastating forms of cognitive decline, which impacts patients’ lives and that of their proxies. Pathologically, AD is characterized by extracellular amyloid deposition, neurofibrillary tangles and chronic neuroinflammation. To date, there is no cure that prevents progression of AD. In this review, we elaborate on how bioactive lipids, including sphingolipids (SL) and specialized pro-resolving lipid mediators (SPM), affect ongoing neuroinflammatory processes during AD and how we may exploit them for the development of new biomarker panels and/or therapies. In particular, we here describe how SPM and SL metabolism, ranging from ω-3/6 polyunsaturated fatty acids and their metabolites to ceramides and sphingosine-1-phosphate, initiates pro- and anti-inflammatory signaling cascades in the central nervous system (CNS) and what changes occur therein during AD pathology. Finally, we discuss novel therapeutic approaches to resolve chronic neuroinflammation in AD by modulating the SPM and SL pathways.

Extracellular Amyloid Deposits in Alzheimer’s and Creutzfeldt–Jakob Disease: Similar Behavior of Different Proteins?

Neurodegenerative diseases are characterized by the deposition of specific protein aggregates, both intracellularly and/or extracellularly, depending on the type of disease. The extracellular occurrence of tridimensional structures formed by amyloidogenic proteins defines Alzheimer’s disease, in which plaques are composed of amyloid β-protein, while in prionoses, the same term “amyloid” refers to the amyloid prion protein. In this review, we focused on providing a detailed didactic description and differentiation of diffuse, neuritic, and burnt-out plaques found in Alzheimer’s disease and kuru-like, florid, multicentric, and neuritic plaques in human transmissible spongiform encephalopathies, followed by a systematic classification of the morphological similarities and differences between the extracellular amyloid deposits in these disorders. Both conditions are accompanied by the extracellular deposits that share certain signs, including neuritic degeneration, suggesting a particular role for amyloid protein toxicity.

Cardiac Amyloidosis: Internist and Cardiologist Insight

Cardiac amyloidosis (amyloid cardiomyopathy) is a disease damage to the heart caused by extracellular amyloid deposition. In some cases, there may be local damage to the structures of the heart, for example, the atria; more often, heart damage is part of a systemic (generalized) pathology. Depending on the amyloid precursor protein, 36 types of amyloidosis are described, among which hereditary and acquired forms are distinguished. Cardiac amyloidosis is diagnosed 1) in the case of the amyloid infiltration in the myocardial bioptates or 2) in the case of non-cardiac amyloid deposition and the left ventricular wall thickening &gt;12 mm without arterial hypertension and other reasons. The heart is most often affected in AL-, ATTR-, AA-, AANF-types of amyloidosis. Cardiac amyloidosis should be considered in patients with a heart failure with an unclear etiology, especially with preserved left ventricular ejection fraction, refractory to treatment, with proteinuria and CKD 4-5, in patients with idiopathic atrial fibrillation and conduction disturbances, in patients with left ventricular wall thickening of unclear etiology, low ECG voltage, unexplained arterial hypotension and pulmonary hypertension. Screening for cardiac amyloidosis should include non-invasive methods such as electrophoresis and immunofixation of blood and urine proteins, the free light lambda and kappa chains of immunoglobulins, 99Tc-DPD scintigraphy, genetic testing (if hereditary variants of amyloidosis are suspected), as well as a histological examination of biopsy samples stained with Congo red and polarizing microscopy.

The Coral Crunch- Amyloidoma

Preface Amyloidoma is an exceptional, progressive disorder constituted by a plethora of conditions with characteristic accumulation of significant quantities of amyloid within soft tissues. Amyloidoma is additionally nomenclated as tumoural amyloidosis or nodular amyloid wherein insulin-derived amyloidoma is referred to as insulin ball. Amyloid nodules may be associated with systemic amyloidosis. Amyloid is a protein polymer configured with identical monomeric protein units. Pathological variety of amyloid is articulated from misfolded proteins. In excess &gt; of twenty-three subtypes of protein can configure amyloid fibres in vivo. Extra-cellular or intra-cellular deposition of amyloid can modify normal organ function [1].

Changes in neuronal excitability and synaptic transmission in nucleus accumbens in a transgenic Alzheimer\u2019s disease mouse model

Several previous studies showed that hippocampus and cortex are affected in Alzheimer’s disease (AD). However, other brain regions have also been found to be affected and could contribute with new critical information to the pathophysiological basis of AD. For example, volumetric studies in humans have shown a significant atrophy of the striatum, particularly in the nucleus Accumbens (nAc). The nAc is a key component of the limbic reward system and it is involved in cognition and emotional behaviors such as pleasure, fear, aggression and motivations, all of which are affected in neurodegenerative diseases such as AD. However, its role in AD has not been extensively studied. Therefore, using an AD mouse model, we investigated if the nAc was affected in 6 months old transgenic 2xTg (APP/PS1) mice. Immunohistochemistry (IHC) analysis in 2xTg mice showed increased intraneuronal Aβ accumulation, as well as occasional extracellular amyloid deposits detected through Thioflavin-S staining. Interestingly, the intracellular Aβ pathology was associated to an increase in membrane excitability in dissociated medium spiny neurons (MSNs) of the nAc. IHC and western blot analyses showed a decrease in glycine receptors (GlyR) together with a reduction in the pre- and post-synaptic markers SV2 and gephyrin, respectively, which correlated with a decrease in glycinergic miniature synaptic currents in nAc brain slices. Additionally, voltage-clamp recordings in dissociated MSNs showed a decrease in AMPA- and Gly-evoked currents. Overall, these results showed intracellular Aβ accumulation together with an increase in excitability and synaptic alterations in this mouse model. These findings provide new information that might help to explain changes in motivation, anhedonia, and learning in the onset of AD pathogenesis.

The role of azurocidin in patients with familial Mediterranean fever and AA amyloidosis and its association with cardiovascular risk factors.

Familial Mediterranean fever (FMF) is characterized by sporadic, recurrent attacks of fever and serosal inflammation. AA amyloidosis (AAA) is a disorder characterized by the extracellular tissue deposition of serum amyloid A protein (SAA). Azurocidin is a neutrophil-derived granule protein. We aimed to investigate the significance of azurocidin in FMF and AAA and the correlation between azurocidin levels and carotid artery intima media thickness (CA-IMT) and cardiovascular plaque existence. A sum of 52 FMF patients were enrolled in the study. FMF patients were composed of two groups. Group-1 included 30 patients with non-complicated FMF. Group-2 included 22 patients whom received renal transplantation due to FMF complicated with AAA and being followed up at stable state for at least one year. 24 healthy individuals who matched with FMF patients in terms of age and gender consisted the control group. We found statistically significant difference between patient and control groups in terms of urea (38.52 ± 19.96mg/dl vs 29.08 ± 5.83mg/dl; p = 0.003), creatinine (1.11 ± 0.39mg/dl vs 0.91 ± 0.16mg/dl; p = 0.002), serum uric acid (6.2 ± 2mg/dl vs 4.5 ± 0.9mg/dl; p < 0.001), serum CRP (8.62 ± 9.5mg/dl vs 3.91 ± 3.9mg/dl; p = 0.004), ferritin (151.4 ± 317ng/ml vs 33.3 ± 34ng/ml; p = 0.014), white blood cell (WBC) levels (7.97 ± 2.3 × 103/µL vs 6.6 ± 1.7 × 103/µL; p = 0.018), serum azurocidin levels (137.16 ± 65.62ng/ml vs 102.35 ± 51.61ng/ml; p = 0.015) and mean CA-IMT (0.57 ± 0.15mm vs 0.47 ± 0.07mm; p = 0.001). Comparison of group 1 and group 2 revealed statistically significant differences in terms of urea (26 ± 8mg/dl vs 54 ± 19mg/dl; p < 0.001), creatinine (0.87 ± 0.1mg/dl vs 1.44 ± 0.3mg/dl; p < 0.001), estimated glomerular filtration rate (eGFR) (99 ± 21ml/min/1.73m2 vs 53 ± 16ml/min/1.73m2; p < .001), uric acid (4.9 ± 1.3mg/dl vs 7.6 ± 1.7mg/dl; p < 0.001), ferritin (31.7 ± 27ng/ml vs 292.8 ± 431ng/ml; p = 0.010) and albumin (4.5 ± 0.3g/dl vs 4.1 ± 0.3g/dl; p = 0.001). There was no statistically significant difference between group 1 and group 2 in terms of mean CA-IMT (CA-IMT (M) (mm): 0.54 ± 0.14 vs 0.62 ± 0.17, p = 0.057). Serum azurocidin levels were not significantly different between group 1 and group 2 (121.73 ± 53.24ng/ml vs 158.19 ± 75.77ng/ml; p = 0.061). In multivariate linear regression analysis (variables: MBP, urea, creatinine, eGFR, ferritin, uric acid, CA-IMT) azurocidin was independently associated with urea (t:2.658; p = 0.010) and CA-IMT (t:2.464; p = 0.017). Based on our findings, azurocidin seems to be a good inflammation marker in patients with FMF. Increase in azurocidin levels might be associated with development of amyloidosis. Also, serum azurocidin levels may be used as a predictor of both inflammatory state and cardiovascular risk, especially when used with other markers such as CA-IMT.

Prion biology: implications for Alzheimer's disease therapeutics

The deposition of extracellular amyloid β is one of the hallmarks of Alzheimer's disease and cerebral amyloid angiopathy. The formation of amyloid fibrils is one manifestation of the misfolding and aggregation of amyloid β into a prion conformation, which then induces the misfolding of additional copies of amyloid β in a self-propagating process. Prions were first discovered for the PrP protein,1,2 and are the cause of Creutzfeldt-Jakob disease and bovine spongiform encephalopathy. In 1994, soon after the discovery of PrP-prions, self-propagating forms of unrelated proteins in yeast and other fungi were found to have beneficial, rather than pathological, roles in these organisms.

Excessive Production of Transforming Growth Factor β1 Causes Mural Cell Depletion From Cerebral Small Vessels.

It is increasingly becoming apparent that cerebrovascular dysfunction contributes to the pathogenic processes involved in vascular dementia, Alzheimer’s disease, and other neurodegenerative disorders. Under these pathologic conditions, the degeneration of cerebral blood vessels is frequently accompanied by a loss of mural cells from the vascular walls. Vascular mural cells play pivotal roles in cerebrovascular functions, such as regulation of cerebral blood flow and maintenance of the blood-brain barrier (BBB). Therefore, cerebrovascular mural cell impairment is involved in the pathophysiology of vascular-related encephalopathies, and protecting these cells is essential for maintaining brain health. However, our understanding of the molecular mechanism underlying mural cell abnormalities is incomplete. Several reports have indicated that dysregulated transforming growth factor β (TGFβ) signaling is involved in the development of cerebral arteriopathies. These studies have specifically suggested the involvement of TGFβ overproduction. Although cerebrovascular toxicity via vascular fibrosis by extracellular matrix accumulation or amyloid deposition is known to occur with enhanced TGFβ production, whether increased TGFβ results in the degeneration of vascular mural cells in vivo remains unknown. Here, we demonstrated that chronic TGFβ1 overproduction causes a dropout of mural cells and reduces their coverage on cerebral vessels in both smooth muscle cells and pericytes. Mural cell degeneration was also accompanied by vascular luminal dilation. TGFβ1 overproduction in astrocytes significantly increased TGFβ1 content in the cerebrospinal fluid (CSF) and increased TGFβ signaling-regulated gene expression in both pial arteries and brain capillaries. These results indicate that TGFβ is an important effector that mediates mural cell abnormalities under pathological conditions related to cerebral arteriopathies.

Periodontal Disease and Periodontal Disease-Related Bacteria Involved in the Pathogenesis of Alzheimer's Disease.

Alzheimer’s disease (AD) is the most common cause of dementia, and it exhibits pathological properties such as deposition of extracellular amyloid β (Aβ) and abnormally phosphorylated Tau in nerve cells and a decrease of synapses. Conventionally, drugs targeting Aβ and its related molecules have been developed on the basis of the amyloid cascade hypothesis, but sufficient effects on the disease have not been obtained in past clinical trials. On the other hand, it has been pointed out that chronic inflammation and microbial infection in the brain may be involved in the pathogenesis of AD. Recently, attention has been focused on the relationship between the periodontopathic bacterium Porphylomonas gingivalis and AD. P. gingivalis and its toxins have been detected in autopsy brain tissues from patients with AD. In addition, pathological conditions of AD are formed or exacerbated in mice infected with P. gingivalis. Compounds that target the toxins of P. gingivalis ameliorate the pathogenesis of AD triggered by P. gingivalis infection. These findings indicate that the pathological condition of AD may be regulated by controlling the bacteria in the oral cavity and the body. In the current aging society, the importance of oral and periodontal care for preventing the onset of AD will increase.