Novel Serum Biomarkers of Neurovascular Unit Associated with Cortical Amyloid Deposition.

BACKGROUND: Whether blood biomarkers of neurovascular unit are associated with cortical amyloid deposition on positron emission tomography (PET) imaging remains unclear. OBJECTIVE: To investigate the association between novel serum biomarkers of neurovascular unit, such as protein tyrosine phosphatase receptor type B (PTPRB), gap junction protein alpha-5 (GJA5), adenosine triphosphate-sensitive inward rectifier potassium channel-8 (KCNJ8), and von Willebrand factor (vWF), and cortical amyloid deposition. METHODS: Between 2012 and 2018, 68 elderly individuals with amnestic mild cognitive impairment (32 men and 36 women; mean age 75.2 years) were enrolled. All participants underwent 11C-Pittsburgh compound-B (PiB)-PET, 18F-fluorodeoxyglucose-PET, and measurement of serum PTPRB, GJA5, KCNJ8, and vWF levels using commercially available human enzyme-linked immunosorbent assay kits. Based on the mean cortical standardized uptake value ratio, the participants were divided into two groups: PiB-negative group and PiB-positive group. Serum levels of PTPRB, GJA5, KCNJ8, and vWF were compared between the two groups. Multiple linear regression analysis was performed to investigate the relationship between serum PTPRB, GJA5, KCNJ8, and vWF levels and cortical amyloid deposition. RESULTS: PTPRB and GJA5 levels were significantly lower and KCNJ8 and vWF levels were significantly higher in the PiB-positive group than in the PiB-negative group. PTPRB and GJA5 levels inversely correlated with mean PiB uptake, whereas KCNJ8 and vWF levels positively correlated with mean PiB uptake. CONCLUSION: Serum levels of PTPRB, GJA5, KCNJ8, and vWF correlate with cortical amyloid deposition. These novel blood biomarkers of neurovascular unit are useful for identifying elderly individuals at risk of developing Alzheimer's disease.

Discriminative Accuracy of Plasma Phospho-tau217 for Alzheimer Disease vs Other Neurodegenerative Disorders.

Importance: There are limitations in current diagnostic testing approaches for Alzheimer disease (AD). Objective: To examine plasma tau phosphorylated at threonine 217 (P-tau217) as a diagnostic biomarker for AD. Design, Setting, and Participants: Three cross-sectional cohorts: an Arizona-based neuropathology cohort (cohort 1), including 34 participants with AD and 47 without AD (dates of enrollment, May 2007-January 2019); the Swedish BioFINDER-2 cohort (cohort 2), including cognitively unimpaired participants (n = 301) and clinically diagnosed patients with mild cognitive impairment (MCI) (n = 178), AD dementia (n = 121), and other neurodegenerative diseases (n = 99) (April 2017-September 2019); and a Colombian autosomal-dominant AD kindred (cohort 3), including 365 PSEN1 E280A mutation carriers and 257 mutation noncarriers (December 2013-February 2017). Exposures: Plasma P-tau217. Main Outcomes and Measures: Primary outcome was the discriminative accuracy of plasma P-tau217 for AD (clinical or neuropathological diagnosis). Secondary outcome was the association with tau pathology (determined using neuropathology or positron emission tomography [PET]). Results: Mean age was 83.5 (SD, 8.5) years in cohort 1, 69.1 (SD, 10.3) years in cohort 2, and 35.8 (SD, 10.7) years in cohort 3; 38% were women in cohort 1, 51% in cohort 2, and 57% in cohort 3. In cohort 1, antemortem plasma P-tau217 differentiated neuropathologically defined AD from non-AD (area under the curve [AUC], 0.89 [95% CI, 0.81-0.97]) with significantly higher accuracy than plasma P-tau181 and neurofilament light chain (NfL) (AUC range, 0.50-0.72; P < .05). The discriminative accuracy of plasma P-tau217 in cohort 2 for clinical AD dementia vs other neurodegenerative diseases (AUC, 0.96 [95% CI, 0.93-0.98]) was significantly higher than plasma P-tau181, plasma NfL, and MRI measures (AUC range, 0.50-0.81; P < .001) but not significantly different compared with cerebrospinal fluid (CSF) P-tau217, CSF P-tau181, and tau-PET (AUC range, 0.90-0.99; P > .15). In cohort 3, plasma P-tau217 levels were significantly greater among PSEN1 mutation carriers, compared with noncarriers, from approximately 25 years and older, which is 20 years prior to estimated onset of MCI among mutation carriers. Plasma P-tau217 levels correlated with tau tangles in participants with (Spearman ρ = 0.64; P < .001), but not without (Spearman ρ = 0.15; P = .33), ß-amyloid plaques in cohort 1. In cohort 2, plasma P-tau217 discriminated abnormal vs normal tau-PET scans (AUC, 0.93 [95% CI, 0.91-0.96]) with significantly higher accuracy than plasma P-tau181, plasma NfL, CSF P-tau181, CSF Aß42:Aß40 ratio, and MRI measures (AUC range, 0.67-0.90; P < .05), but its performance was not significantly different compared with CSF P-tau217 (AUC, 0.96; P = .22). Conclusions and Relevance: Among 1402 participants from 3 selected cohorts, plasma P-tau217 discriminated AD from other neurodegenerative diseases, with significantly higher accuracy than established plasma- and MRI-based biomarkers, and its performance was not significantly different from key CSF- or PET-based measures. Further research is needed to optimize the assay, validate the findings in unselected and diverse populations, and determine its potential role in clinical care.

Increased plasma bradykinin level is associated with cognitive impairment in Alzheimer's patients.

Alzheimer's disease (AD) is characterized by the presence of proteinaceous brain deposits, brain atrophy, vascular dysfunction, and chronic inflammation. Along with cerebral inflammation, peripheral inflammation is also evident in many AD patients. Bradykinin, a proinflammatory plasma peptide, is also linked to AD pathology. For example, bradykinin infusion into the hippocampus causes learning and memory deficits in rats, and blockade of the bradykinin receptor lessens cognitive impairment in AD mouse models. Even though it has been hypothesized that plasma bradykinin could contribute to inflammation in AD, the level of plasma bradykinin and its association with beta-amyloid (Aß) pathology in AD patients had not been explored. Here, we assessed plasma bradykinin levels in AD patients and age-matched non-demented (ND) control individuals. We found significantly elevated plasma bradykinin levels in AD patients compared to ND subjects. Additionally, changes in plasma bradykinin levels were more profound in many AD patients with severe cognitive impairment, suggesting that peripheral bradykinin could play a role in dementia most likely via inflammation. Bradykinin levels in the cerebrospinal fluid (CSF) were reduced in AD patients and exhibited an inverse correlation with the CSF Aß40/Aß42 ratio. We also report that bradykinin interacts with the fibrillar form of Aß and co-localizes with Aß plaques in the post-mortem human AD brain. These findings connect the peripheral inflammatory pathway to cerebral abnormalities and identify a novel mechanism of inflammatory pathology in AD.

Serum amyloid A1 is involved in amyloid plaque aggregation and memory decline in amyloid beta abundant condition.

Alzheimer's disease (AD) is a neurodegenerative disorder, characterized by cognitive impairment, progressive neurodegeneration, and amyloid-ß (Aß) lesion. In the neuronal death and disease progression, inflammation is known to play an important role. Our previous study on acute-phase protein serum amyloid A1 (SAA1) overexpressed mice showed that the liver-derived SAA1 accumulated in the brain by crossing the brain blood barrier (BBB) and trigger the depressive-like behavior on mouse. Since SAA1 involved in immune responses in other diseases, we focused on the possibility that SAA1 may exacerbate the neuronal inflammation related to Alzheimer's disease. A APP/SAA overexpressed double transgenic mouse was generated using amyloid precursor protein overexpressed (APP)-c105 mice and SAA1 overexpressed mice to examine the function of SAA1 in Aß abundant condition. Comparisons between APP and APP/SAA1 transgenic mice showed that SAA1 exacerbated amyloid aggregation and glial activation; which lead to the memory decline. Behavior tests also supported this result. Overall, overexpression of SAA1 intensified the neuronal inflammation in amyloid abundant condition and causes the greater memory decline compared to APP mice, which only expresses Aß 1-42.

Amyloidogenic Nanoplaques in Blood Serum of Patients with Alzheimer's Disease Revealed by Time-Resolved Thioflavin T Fluorescence Intensity Fluctuation Analysis.

BACKGROUND: Biomarkers are central to current research on molecular mechanisms underlying Alzheimer's disease (AD). Their further development is of paramount importance for understanding pathophysiological processes that eventually lead to disease onset. Biomarkers are also crucial for early disease detection, before clinical manifestation, and for development of new disease modifying therapies. OBJECTIVE: The overall aim of this work is to develop a minimally invasive method for fast, ultra-sensitive and cost-effective detection of structurally modified peptide/protein self-assemblies in the peripheral blood and in other biological fluids. Specifically, we focus here on using this method to detect structured amyloidogenic oligomeric aggregates in the blood serum of apparently healthy individuals and patients in early AD stage, and measure their concentration and size. METHODS: Time-resolved detection of Thioflavin T (ThT) fluorescence intensity fluctuations in a sub-femtoliter observation volume element was used to identify in blood serum ThT-active structured amyloidogenic oligomeric aggregates, hereafter called nanoplaques, and measure with single-particle sensitivity their concentration and size. RESULTS: The concentration and size of structured amyloidogenic nanoplaques are significantly higher in the blood serum of individuals diagnosed with AD than in control subjects. CONCLUSION: A new method with the ultimate, single-particle sensitivity was successfully developed. The proposed approach neither relies on the use of immune-based probes, nor on the use of radiotracers, signal-amplification or protein separation techniques, and provides a minimally invasive test for fast and cost-effective early determination of structurally modified peptides/proteins in the peripheral blood, as shown here, but also in other biological fluids.

Apolipoprotein E4 Mediates the Association Between Midlife Dyslipidemia and Cerebral Amyloid in Aging Women.

Cerebral amyloid-ß (Aß) plaques are the hallmark biomarker of Alzheimer's disease (AD) and are detectable decades before clinical symptoms. Modifying risk factors associated with Aß accrual offers an opportunity for AD prevention. While midlife vascular health is linked to AD; there is minimal longitudinal evidence regarding the effect of midlife lipids on Aß. We examined the association between midlife lipids and Aß 20 years later. One hundred and twenty-two women had serum lipid profiles in midlife (1992, 45-57 years), and cerebral imaging, genotyping, and cognition measured 20 years later (2012/13, 66-77 years). Imaging was performed in 2012/13 via F-18 Florbetaben positron emission tomography (PET) and standard uptake value ratios (SUVR) were calculated. Lipid profiles and other predictors of high PET-SUVR levels (>1.2) were evaluated using multivariable logistic regression. Increases in low-density lipoprotein (LDL) cholesterol in midlife were associated with Aß, adjusting for age, education, cholesterol medication, and cognition (AdjOR1.81, 95% CI 1.08-3.01, p = 0.024), but attenuated on adjustment for apolipoprotein E4 (APOE ɛ4). Aß risk increased in women with APOE ɛ4 and midlife cholesterol >6.2 mmol/L (AdjOR9.59, 95% CI 2.94-31.31, p < 0.001), APOE ɛ4 and LDL >3.3 mmol/L (AdjOR9.00, 95% CI 2.89-28.03, p < 0.001), and APOE ɛ4 and cholesterol to high-density lipoprotein ratio ≥3.25 (AdjOR8.32, 95% CI 2.32-29.89, p < 0.001). Presence of APOE ɛ4 and midlife dyslipidemia compounded the risk for Aß deposition, although no independent effect of midlife lipids was found. Lipid-modifying treatment in midlife could mitigate the risk of Aß in women with a genetic predisposition for AD. To better inform prevention, future consideration should be given toward managing dyslipidemia in women carrying the APOE ɛ4 allele.

Correlation of Serum Uric Acid Levels with Nonculprit Plaque Instability in Patients with Acute Coronary Syndromes: A 3-Vessel Optical Coherence Tomography Study.

Elevated serum uric acid (SUA) level is known to be a prognostic factor in patients with acute coronary syndrome (ACS). However, the correlation between SUA level and coronary plaque instability has not been fully evaluated. The aim of this study was to investigate the association between SUA level and plaque instability of nonculprit lesions in patients with ACS using optical coherence tomography. A total of 150 patients with ACS who underwent 3-vessel optical coherence tomography were selected. Patients were classified into 3 groups according to tertiles of SUA level. There was a trend towards a thinner fibrous cap (0.15 ± 0.06 versus 0.07 ± 0.01 versus 0.04 ± 0.01 mm2, p < 0.001) and a wider mean lipid arc (169.41 ± 33.16 versus 177.22 ± 37.76 versus 222.43 ± 47.65°, p < 0.001) with increasing SUA tertile. The plaques of the high and intermediate tertile groups had a smaller minimum lumen area than the low tertile group (6.02 ± 1.11 versus 5.38 ± 1.28 mm2, p < 0.001). In addition, thin-cap fibroatheromas, microvessels, macrophages, and cholesterol crystals were more frequent in the high tertile group than the low and intermediate groups. Multivariate analysis showed SUA level to be a predictor of plaque instability.

Plasma Aß analysis using magnetically-labeled immunoassays and PET 18F-florbetapir binding in non-demented patients with major depressive disorder.

An increased level of brain amyloid deposition and a decreased level of cerebral spinal fluid (CSF) Aß42 are currently considered reliable biomarkers of Alzheimer's disease (AD); however, the usefulness of plasma Aß levels are not well-established. This study investigated the relationships between plasma Aß levels and cerebral amyloidosis in 36 non-demented patients with major depressive disorder (MDD). All participants underwent 18F-florbetapir PET imaging and provided a blood sample at the same time for immunomagnetic reduction assay to measure the plasma levels of Aß40 and Aß42. We found inverse associations of the plasma Aß42 level and the Aß42/Aß40 ratio, and a positive association of the plasma Aß40 level, with cerebral amyloid deposition in the precuneus, parietal and posterior cingulate cortex. Subgroup analyses in subjects with higher 18F-florbetapir uptake values or MDD with amnestic mild cognitive impairment revealed more pervasive relationships of plasma Aß measures with 18F-florbetapir binding across the brain regions examined. The study suggested that regional brain amyloid deposition in terms of 18F-florbetapir PET uptake had weak-to-moderate associations with plasma Aß42 and Aß40 levels, and the Aß42/Aß40 ratio. Validation in a larger population of subjects of known cerebral amyloidosis status is needed. Careful interpretation of plasma data is warranted.

Proximate Mediators of Microvascular Dysfunction at the Blood-Brain Barrier: Neuroinflammatory Pathways to Neurodegeneration.

Current projections are that by 2050 the numbers of people aged 65 and older with Alzheimer's disease (AD) in the US may increase threefold while dementia is projected to double every 20 years reaching ~115 million by 2050. AD is clinically characterized by progressive dementia and neuropathologically by neuronal and synapse loss, accumulation of amyloid plaques, and neurofibrillary tangles (NFTs) in specific brain regions. The preclinical or presymptomatic stage of AD-related brain changes may begin over 20 years before symptoms occur, making development of noninvasive biomarkers essential. Distinct from neuroimaging and cerebrospinal fluid biomarkers, plasma or serum biomarkers can be analyzed to assess (i) the presence/absence of AD, (ii) the risk of developing AD, (iii) the progression of AD, or (iv) AD response to treatment. No unifying theory fully explains the neurodegenerative brain lesions but neuroinflammation (a lethal stressor for healthy neurons) is universally present. Current consensus is that the earlier the diagnosis, the better the chance to develop treatments that influence disease progression. In this article we provide a detailed review and analysis of the role of the blood-brain barrier (BBB) and damage-associated molecular patterns (DAMPs) as well as coagulation molecules in the onset and progression of these neurodegenerative disorders.

Chemically treated plasma Aß is a potential blood-based biomarker for screening cerebral amyloid deposition.

BACKGROUND: Plasma ß-amyloid (Aß) is a potential candidate for an Alzheimer's disease (AD) biomarker because blood is an easily accessible bio-fluid, which can be collected routinely, and Aß is one of the major hallmarks of AD pathogenesis in the brain. However, the association between plasma Aß levels and AD diagnosis is still unclear due to the instability and inaccurate measurements of plasma Aß levels in the blood of patients with AD. If a consistent value of plasma Aß from the blood can be obtained, this might help determine whether plasma Aß is a potential biomarker for AD diagnosis. METHODS: We predicted the brain amyloid deposit by measuring the plasma Aß levels. This cross-sectional study included 353 participants (215 cognitively normal, 79 with mild cognitive impairment, and 59 with AD dementia) who underwent Pittsburgh-compound B positron emission tomography (PiB-PET) scans. We treated a mixture of protease inhibitors and phosphatase inhibitors (MPP) and detected plasma Aß42 and Aß40 (MPP-Aß42 and MPP-Aß40) in a stable manner using xMAP technology. RESULTS: MPP-Aß40 and MPP-Aß42/40 (MPP-Aßs) were significantly different between subjects with positive amyloid deposition (PiB+) and those with negative amyloid deposition (PiB-) (P < 0.0001). Furthermore, MPP-Aß40 (P < 0.0001, r = 0.23) and MPP-Aß42/40 ratio (P < 0.0001, r = -0.23) showed significant correlation with global PiB deposition (standardized uptake value ratio). In addition, our integrated multivariable (MPP-Aß42/40, gender, age, and apolipoprotein E genotypes) logistic regression model proposes a new standard for the prediction of cerebral amyloid deposition. CONCLUSIONS: MPP-Aß might be one of the potential blood biomarkers for the prediction of PiB-PET positivity in the brain.

Age-dependent inverse correlations in CSF and plasma amyloid-ß(1-42) concentrations prior to amyloid plaque deposition in the brain of 3xTg-AD mice.

Amyloid-ß (Aß) plays a critical role as a biomarker in Alzheimer's disease (AD) diagnosis. In addition to its diagnostic potential in the brain, recent studies have suggested that changes of Aß level in the plasma can possibly indicate AD onset. In this study, we found that plasma Aß(1-42) concentration increases with age, while the concentration of Aß(1-42) in the cerebrospinal fluid (CSF) decreases in APPswe, PS1M146V and TauP301L transgenic (3xTg-AD) mice, if measurements were made before formation of ThS-positive plaques in the brain. Our data suggests that there is an inverse correlations between the plasma and CSF Aß(1-42) levels until plaques form in transgenic mice's brains and that the plasma Aß concentration possesses the diagnostic potential as a biomarker for diagnosis of early AD stages.

Dialysis Amyloid Deposition in the Aortic Valve and Its Association with Aortic Stenosis.

BACKGROUND: The relationship between dialysis amyloid (DA) deposition in the aortic valve (AV) and aortic stenosis (AS) is unknown. METHODS: This was a cross-sectional study. AV specimens of dialysis patients (median vintage: 8.8 years) consecutively collected from cardiac surgeries (n = 56) or autopsies (n = 13) were examined by a board-certified pathologist blinded to clinical data. DAs were considered to be present if deposits were stained both by Congo red with apple-green birefringence under polarized light and by anti-ß2-microblobulin antibody. Degree of deposition was graded as follows: Amyloid (-), no deposit; Amyloid (1+), occasional small deposits; Amyloid (2+), multiple small to large deposits or a single large deposit. Calcification was defined as a calcified deposit with a diameter >1 mm in the specimen. Severe AS (sAS) was defined as a mean gradient >50 mm Hg by echocardiogram. We examined the proportion of DAs and the association between DAs and the sAS. RESULTS: DAs were present in 71% (n = 49) of specimens and primarily co-localized with calcification. Non-dialysis related amyloid was found in one specimen. After excluding this specimen, sAS was associated with 'Amyloid (1+) and Calcification >1 mm' and 'Amyloid (2+) and Calcification >1 mm' (vs. 'Amyloid (-) and Calcification ≤1 mm', odds ratios (ORs): 13.5 and 34.2, respectively). Furthermore, after adjustment for covariates, sAS was found to be associated with 'Amyloid (2+) and Calcification >1 mm' (OR: 24.3). CONCLUSIONS: DA deposition in the AV was prevalent among dialysis patients. DA deposition with accompanying calcification might contribute to the severity of AS.

Plaque array method and proteomics-based identification of biomarkers from Alzheimer's disease serum.

BACKGROUND: Progressive accumulation of amyloid plaques in the regions of brain, carotid and cerebral arteries is the leading cause of Alzheimer's disease (AD) and related dementia in affected patients. The early identification of individuals with AD remains a challenging task relying on symptomatic events and thus the development of a biomarker-based approach will significantly aid in the diagnosis of AD. METHODS: Here we describe a flow cytometer-based serum biomarker identification method using plaque particles, and applying mass spectrometry based proteomic analysis of the isolated plaque particles for the identification of serum proteins present in the plaque particles. RESULTS: We identified 195 serum proteins that participate in the process of plaque particle formation. Among the 195 proteins identified, 68.2% of them overlapped in abeta-42, cholesterol, tau-275 and α-synuclein plaque particles. Significantly, 22.5% of the proteins identified as bound to abeta-42 plaque particles generated in AD serum were unique when compared with cholesterol, α-synuclein and tau plaque particles. In age-matched control experiments, 15% of them showed in vitro insoluble abeta-42 particle formation and 59% of the identified plaque particle constituents from AD serum were also present in the insoluble plaque particles derived from control. CONCLUSIONS: We have developed an in vitro method for plaque particle detection and identified serum protein markers that are associated with AD-related plaque particle formation. With further clinical validation, this assay may provide a novel, non-invasive means for the early detection of AD.

Elevated mRNA-levels of gonadotropin-releasing hormone and its receptor in plaque-bearing Alzheimer's disease transgenic mice.

Research on Alzheimer's disease (AD) has indicated an association between hormones of the hypothalamic-pituitary-gonadal (HPG) axis and cognitive senescence, indicating that post meno-/andropausal changes in HPG axis hormones are implicated in the neuropathology of AD. Studies of transgenic mice with AD pathologies have led to improved understanding of the pathophysiological processes underlying AD. The aims of this study were to explore whether mRNA-levels of gonadotropin-releasing hormone (Gnrh) and its receptor (Gnrhr) were changed in plaque-bearing Alzheimer's disease transgenic mice and to investigate whether these levels and amyloid plaque deposition were downregulated by treatment with a gonadotropin-releasing hormone analog (Gnrh-a; Leuprorelin acetate). The study was performed on mice carrying the Arctic and Swedish amyloid-ß precursor protein (AßPP) mutations (tgArcSwe). At 12 months of age, female tgArcSwe mice showed a twofold higher level of Gnrh mRNA and more than 1.5 higher level of Gnrhr mRNA than age matched controls. Male tgArcSwe mice showed the same pattern of changes, albeit more pronounced. In both sexes, Gnrh-a treatment caused significant down-regulation of Gnrh and Gnrhr mRNA expression. Immunohistochemistry combined with quantitative image analysis revealed no significant changes in the plaque load after Gnrh-a treatment in hippocampus and thalamus. However, plaque load in the cerebral cortex of treated females tended to be lower than in female vehicle-treated mice. The present study points to the involvement of hormonal changes in AD mice models and demonstrates that these changes can be effectively counteracted by pharmacological treatment. Although known to increase in normal aging, our study shows that Gnrh/Gnrhr mRNA expression increases much more dramatically in tgArcSwe mice. Treatment with Leuprorelin acetate successfully abolished the transgene specific effects on Gnrh/Gnrhr mRNA expression. The present experimental approach should serve as a platform for further studies on the usefulness of Gnrh-a treatment in suppressing plaque development in AD.

Behavioral stress fails to accelerate the onset and progression of plaque pathology in the brain of a mouse model of Alzheimer's disease.

Conflicting findings exist regarding the link between environmental factors and development of Alzheimer's disease (AD) in a variety of transgenic mouse models of AD. In the present study, we investigated the effect of behavioral stress on the onset and progression of Aß pathology in the brains of TgCRND8 mice, a transgenic mouse model of AD. One group of TgCRND8 mice was subjected to restraint stress starting at 1 month of age until they were 3 months old, while restraint stress in the second group started at 4 months of age until they were 6 months old. After 2 months of treatment, no differences in the soluble, formic acid extracted, or histologically detected Aß deposition in the cortical and hippocampal levels were found between non-stressed and stressed mice. These results showed that restraint stress alone failed to aggravate amyloid pathology when initiated either before or after the age of amyloid plaque deposition in TgCRND8 mice, suggesting that if stress aggravated AD phenotype, it may not be via an amyloid-related mechanism in the TgCRND8 mice. These findings are indicative that plaque load per se may not be used as a significant criterion for evaluating the effect of stress on AD patients.

Atypical AA amyloid deposits in bovine AA amyloidosis.

In bovine amyloid protein A (AA) amyloidosis, amyloid deposits are typically observed in the kidney and spleen at necropsy. To determine the distribution of amyloid deposits in cows affected with AA amyloidosis, we examined organs known to be sites of amyloid deposits that are also processed for human consumption in 14 cows: 11 with typical clinical symptoms (typical amyloidosis) and three with no typical clinical symptoms (atypical amyloidosis). We found unusually high amounts of amyloid deposits in the tongue and other organs in all 14 cows regardless of the presence or absence of clinical amyloidosis symptoms. Cows with typical amyloidosis had heavier amyloid deposits in the spleen and renal glomeruli than cows with atypical amyloidosis. From clinical symptoms and histological examinations, we found that cows with typical and atypical amyloidosis can be classified into two groups, class I and class II, according to the presence or absence of heavy amyloid deposits in the spleen and renal glomeruli. However, no significant differences were observed between the amyloid fibrils of class I and class II amyloidosis by electron microscopy and Western blot analysis.

Antisense oligonucleotide suppression of serum amyloid A reduces amyloid deposition in mice with AA amyloidosis.

AA amyloid patients who experience disease progression and develop renal failure have not received sufficient benefit from agents that treat inflammation or infection. We have begun to explore the potential application of antisense oligonucleotides (ASOs) to specifically suppress SAA production and thereby reduce amyloid deposition. Proof-of-concept experiments conducted in mice initially examined ASO ability to reduce serum levels of SAA during an acute inflammatory response. Peak SAA levels in ASO-treated mice were reduced as much as 65% relative to levels in saline-treated mice. The extent of suppression was dose-dependent and influenced by the time interval between ASO administration and inflammatory stimulation. Subsequent experiments tested whether ASO suppression of SAA was sufficient to mitigate amyloid deposition. Amyloidosis was induced by amyloid-enhancing factor and silver nitrate injection; ASO treatment was initiated 1 week later and continued 1× or 3× per week; inflammation was re-triggered by subsequent injection(s) of silver nitrate; mice were sacrificed after 4-5 weeks. Examination of tissues by Congo red staining and SAA/AA immunohistochemistry revealed consistently less amyloid in the organs of ASO-treated mice compared to saline-treated counterparts. These findings provide rationale for further investigation of SAA-specific ASOs as a potential therapy for AA amyloidosis.

Colocalisation of plasma derived apo B lipoproteins with cerebral proteoglycans in a transgenic-amyloid model of Alzheimer's disease.

Alzheimer's disease (AD) is characterized by cerebral proteinaceous deposits comprised of amyloid beta (Aß). Evidence suggests that enhanced blood-to-brain delivery of Aß occurs when plasma concentration is increased, exacerbating amyloidosis. In blood, significant Aß is associated with apolipoprotein (apo) B lipoproteins. In this study, immunofluorescent microscopy was utilised to explore if there is an association between apo B lipoproteins and proteoglycan expression within Aß-rich plaques in transgenic-amyloid mice. Focal accumulation of apo B was found with Aß-plaque in APP/PS1 mice. There was enrichment in the proteoglycans, agrin, perlecan, biglycan and decorin within the core of dense Aß-plaque. Perlecan, biglycan and decorin were positively associated with apo B lipoprotein abundance within amyloid plaque consistent with a cause-for-retention effect. These findings show that proteoglycans are an integral component of Aß deposits in APP/PS1 mice. This study suggests that some proteoglycans contribute to Aß retention, whilst other proteoglycans have different functions in the aetiology of AD.