Amyloid-β Research Articles

A - 117 Double Trouble: a Case Study on Cardiac Amyloidosis and Alzheimer’s Disease

Abstract Objective Transthyretin amyloidosis (ATTR) is an increasingly recognized cause of heart failure amongst older adults. The median age upon diagnosis is 75 with 90% of patients reported as men. The amyloidogenic protein is transthyretin (TTR), which is primarily produced in the liver, but is also produced in the choroid plexus and neurons under distress. There are two types of ATTR: an autosomal dominant and a wild-type (wt) variant. ATTRwt is the amyloid precursor in the cardiac depositions found in older adults. We present the first neuropsychological evaluation of a patient with ATTRwt. Method An 87-year-old right-handed White woman reported a 2 year history of slowly progressive short term memory decline. Her family noted rapid cognitive decline and paranoia approximately 6 months ago. Medical history was notable for heart failure, along with lumbar stenosis, carpal tunnel syndrome, arthritis, scoliosis, and hyperlipidemia. ATTRwt diagnosis was made during cardiac clearance for lumbar surgery. Neuroimaging documented age-related cerebral atrophy and chronic microvascular ischemic disease. Results Inspection of data revealed an amnestic presentation, with impaired confrontational naming, spatial judgment, and processing speed performances. She denied depressogenic and anxiolytic symptoms while family endorsed symptoms of apathy and executive dysfunction. Conclusions The relationship between cardiac and nervous systems has garnished increasing attention in the literature and in clinical planning. Overall, the relationship between cardiac TTR amyloid and brain amyloid beta deposition in humans is unclear. Neuropsychologists should be aware of this heart condition that is increasingly recognized in older adults and the intriguing findings implicated around the cardiac-brain axis.

Associations between misfolded alpha-synuclein aggregates and Alzheimer's disease pathology in vivo.

We examined the relations of misfolded alpha synuclein (α-synuclein) with Alzheimer's disease (AD) biomarkers in two large independent cohorts. We included Biomarkers for Identifying Neurodegenerative Disorders Early and Reliably Two (BioFINDER-2) and Alzheimer's Disease Neuroimaging Initiative (ADNI) participants (n=2315, cognitively unimpaired, mild cognitive impairment, AD dementia) who had cross-sectional cerebrospinal fluid (CSF) α-synuclein measurement from seed-amplification assay as well as cross-sectional and longitudinal amyloid beta (Aβ) and tau levels (measured in CSF and/or by positron emission tomography). All analyses were adjusted for age, sex, and cognitive status. Across cohorts, the main biomarker associated with α-synuclein positivity at baseline was higher levels of Aβ pathology (all p values≤0.02), but not tau. Looking at longitudinal measures of AD biomarkers, α-synuclein -positive participants had a statistically significant faster increase of Aβ load, although of modest magnitude (1.11 Centiloid/year, p=0.02), compared to α-synuclein -negative participants in BioFINDER-2 but not in ADNI. We showed associations between concurrent misfolded α-synuclein and Aβ levels, providing in vivo evidence of links between these two molecular disease pathways in humans. Amyloid beta (Aβ), but not tau, was associated with alpha-synuclein (α-synuclein) positivity. Such association was consistent across two cohorts, beyond the effect of age, sex, and cognitive status. α-synuclein-positive participants had a small, statistically significant faster increase in Aβ positron emission tomography levels in one of the two cohorts.

Cognitive resilience to Alzheimer's disease characterized by cell-type abundance.

The molecular basis of cognitive resilience (CR) among pathologically confirmed Alzheimer's disease (AD) cases is not well understood. Abundance of 13 cell types and neuronal subtypes in brain bulk RNA-seq data from the anterior caudate, dorsolateral prefrontal cortex (DLPFC), and posterior cingulate cortex (PCC) obtained from 434 AD cases, 318 cognitively resilient AD cases, and 188 controls in the Religious Orders Study and Rush Memory and Aging Project was estimated by deconvolution. PVALB+ neuron abundance was negatively associated with cognitive status and tau pathology in the DLPFC and PCC (Padj<0.001) and the most reduced neuronal subtype in AD cases compared to controls in DLPFC (Padj=8.4×10-7) and PCC (Padj=0.0015). We identified genome-wide significant association of neuron abundance with TMEM106B single nucleotide polymorphism rs13237518 in PCC (p=6.08×10-12). rs13237518 was also associated with amyloid beta (p=0.0085) and tangles (p=0.0073). High abundance of PVALB+ neurons may be a marker of CR. TMEM106B variants may influence CR independent of AD pathology. Neuron retention and a lack of astrocytosis are highly predictive of Alzheimer's disease (AD) resilience. PVALB+ GABAergic and RORB+ glutamatergic neurons are associated with cognitive status. A TMEM106B single nucleotide polymorphism is related to lower AD risk, higher neuron count, and increased AD pathology.

Inhibition of Amyloid β Accumulation by Protease-Digested Whitebait (Shirasu) in a Murine Model of Alzheimer's Disease.

The number of people with dementia is increasing annually worldwide. Alzheimer's disease (AD), which accounts for the highest percentage of dementia-causing diseases, remains difficult to cure, and prevention of its onset is important. We aimed to discover new AD-preventive ingredients and investigate the inhibitory effects of ten different species of seafood digests prepared by protease treatment on β-secretase 1 (BACE1) activity. Substantial inhibition of BACE1 activity was observed in five species of seafood, and protease-digested whitebait (WPD) showed the highest inhibitory effect among the ten marine samples. We further examined the potential of WPD as an AD preventive component using a familial AD strain (5xFAD) murine model. The intraperitoneal administration of WPD for 28 days substantially decreased the insoluble amyloid β1-42 content and the expression of glial fibrillary acidic protein, a marker of astrogliosis, in the cerebral cortex of the 5xFAD mice. These results strongly suggest that WPD is a novel functional food-derived ingredient with preventive effects against AD.

8-weeks aerobic exercise ameliorates cognitive deficit and mitigates ferroptosis triggered by iron overload in the prefrontal cortex of APP Swe/PSEN 1dE9 mice through Xc-/GPx4 pathway.

Alzheimer's disease (AD) is a degenerative disorder of the central nervous system characterized by notable pathological features such as neurofibrillary tangles and amyloid beta deposition. Additionally, the significant iron accumulation in the brain is another important pathological hallmark of AD. Exercise can play a positive role in ameliorating AD, but the mechanism is unclear. The purpose of the study is to explore the effect of regular aerobic exercise iron homeostasis and lipid antioxidant pathway regarding ferroptosis in the prefrontal cortex (PFC) of APP Swe/PSEN 1dE9 (APP/PS1) mice. Eighty 6-month-old C57BL/6 J and APP/PS1 mice were divided equally into 8-weeks aerobic exercise groups and sedentary groups. Subsequently, Y-maze, Morris water maze test, iron ion detection by probe, Western Blot, ELISA, RT-qPCR, HE, Nissle, Prussian Blue, IHC, IF, and FJ-C staining experiments were conducted to quantitatively assess the behavioral performance, iron levels, iron-metabolism-related proteins, lipid antioxidant-related proteins and morphology in each group of mice. In APP/PS1 mice, the increase in heme input proteins and heme oxygenase lead to the elevated levels of free iron in the PFC. The decrease in ferritin content by ferritin autophagy fails to meet the storage needs for excess free iron within the nerve cells. Ultimately, the increase of free ferrous iron triggers the Fenton reaction, may lead to ferroptosis and resulting in cognitive impairment in APP/PS1 mice. However, 8-weeks aerobic exercise induce upregulation of the Xc-/GPx4 pathway, which can reverse the lipid peroxidation process, thereby inhibiting ferroptosis in APP/PS1 mice. 8 weeks aerobic exercise can improve learning and memory abilities in AD, upregulate GPx4/Xc- pathway in PFC to reduce ferroptosis induced by AD.

Membrane-assisted Aβ40 aggregation pathways.

Alzheimer's disease (AD) is caused by the assembly of amyloid-beta (Aβ) peptides into oligomers and fibrils. Endogenous Aβ aggregation may be assisted by cell membranes, which can accelerate the nucleation step enormously, but knowledge of membrane-assisted aggregation is still very limited. Here we used extensive MD simulations to structurally and energetically characterize key intermediates along the membrane-assisted aggregation pathways of Aβ40. Reinforcing experimental observations, the simulations reveal unique roles of GM1 ganglioside and cholesterol in stabilizing membrane-embedded β-sheets and of Y10 and K28 in the ordered release of a small oligomeric seed into solution. The same seed leads to either an open-shaped or R-shaped fibril, with significant stabilization provided by inter- or intra-subunit interfaces between a straight β-sheet (residues Q15-D23) and a bent β-sheet (residues A30-V36). This work presents the first comprehensive picture of membrane-assisted aggregation of Aβ40, with broad implications for developing AD therapies and rationalizing disease-specific polymorphisms of amyloidogenic proteins.

Computational identification of promising therapeutics via BACE1 Targeting: Implications for Alzheimer's disease.

Alzheimer's disease (AD) is a significant global healthcare challenge, particularly in the elderly population. This neurodegenerative disorder is characterized by impaired memory and progressive decline in cognitive function. BACE1, a transmembrane protein found in neurons, oligodendrocytes, and astrocytes, exhibits varying levels across different neural subtypes. Abnormal BACE1 activity in the brains of individuals with AD leads to the formation of beta-amyloid proteins. The complex interplay between myelin sheath formation, BACE1 activity, and beta-amyloid accumulation suggests a critical role in understanding the pathological mechanisms of AD. The primary objective of this study was to identify molecular inhibitors that target Aβ. Structure-based virtual screening (SBVS) was employed using the MCULE database, which houses over 2 million chemical compounds. A total of 59 molecules were selected after the toxicity profiling. Subsequently, five compounds conforming to the Egan-Egg permeation predictive model of the ADME rules were selected and subjected to molecular docking using AutoDock Vina on the Mcule drug discovery platform. The top two ligands and the positive control, 5HA, were subjected to molecular dynamics simulation for five nanoseconds. Toxicity profiling, physiochemical properties, lipophilicity, solubility, pharmacokinetics, druglikeness, medicinal chemistry attributes, average potential energy, RMSD, RMSF, and Rg analyses were conducted to identify the ligand MCULE-9199128437-0-2 as a promising inhibitor of BACE1.

Design, synthesis, and biological evaluation of tetrahydropyrimidine analogue as GSK-3β/Aβ aggregation inhibitor and anti-Alzheimer’s agent

The complex nature of Alzheimer’s disease (AD) etiopathology is among the principal hurdles to developing effective anti-Alzheimer agents. Tau pathology and Amyloid-β (Aβ) accumulation are hallmarks and validated therapeutic strategies of AD. GSK-3β is a serine/threonine kinase involved in tau phosphorylation. Its excessive activity also contributes to the production of Aβ plaques, making GSK-3β an attractive AD target. Taking this into account, In this article, we outline the design, synthesis, and biological validation of a focused library of 1,2,3,4-tetrahydropyrimidine based derivatives as inhibitors of GSK-3β, tau phosphorylation, and Aβ accumulation. The inhibitory activity of forty nine synthetic compounds was tested against GSK-3β and other AD-relevant kinases. The kinetic experiments revealed the mode of GSK-3β inhibition by the most potent compound 44. The in- vitro drug metabolism and pharmacokinetic studies were thereafter performed. The anti-aggregation activity of the most potent GSK-3β inhibitor was tested using AD transgenic Caenorhabditis elegans (C. elegans) strain CL2006 for quantification of Aβ plaques and BR5706 C. elegans strain for tau pathology evaluation. We then evaluated the blood–brain barrier permeability and got promising results. Therefore, we present compound 44 as a potential ATP-competitive GSK-3β inhibitor with good metabolism and pharmacokinetic profile, anti-aggregation properties for amyloid beta protein, and reduction in tau-phosphorylation levels. We recommend more investigation into compound 44-based small molecules as possible targets for AD disease-modifying treatments.

Minocycline mitigates Aβ and TAU pathology, neuronal dysfunction, and death in the PSEN1 E280A cholinergic-like neurons model of familial Alzheimer’s disease

Familial Alzheimer’s disease (FAD) presenilin 1 E280A (PSEN1 E280A) is a severe neurological condition due to the loss of cholinergic neurons (ChNs), accumulation of amyloid beta (Aβ), and abnormal phosphorylation of the TAU protein. Up to date, there are no effective therapies available. The need for innovative treatments for this illness is critical. We found that minocycline (MC, 5 μM) was innocuous toward wild-type (WT) PSEN1 ChLNs but significantly (i) reduces the accumulation of intracellular Aβ by −69%, (ii) blocks both abnormal phosphorylation of the protein TAU at residue Ser202/Thr205 by −33% and (iii) phosphorylation of the proapoptotic transcription factor c-JUN at residue Ser63/Ser73 by −25%, (iv) diminishes oxidized DJ-1 at Cys106-SO3 by −29%, (v) downregulates the expression of transcription factor TP53, (vi) BH-3-only protein PUMA, and (vii) cleaved caspase 3 (CC3) by −33, −86, and −78%, respectively, compared with untreated PSEN1 E280A ChLNs. Additionally, MC increases the response to ACh-induced Ca2+ influx by +92% in mutant ChLNs. Oxygen radical absorbance capacity (ORAC) and ferric ion-reducing antioxidant power (FRAP) analysis showed that MC might operate more efficiently as a hydrogen atom transfer agent than a single electron transfer agent. In silico molecular docking analysis predicts that MC binds with high affinity to Aβ (Vina Score −6.6 kcal/mol), TAU (VS -6.5 kcal/mol), and caspase 3 (VS -7.1 kcal/mol). Taken together, our findings suggest that MC demonstrates antioxidant, anti-amyloid, and anti-apoptosis activity and promotes physiological ACh-induced Ca2+ influx in PSEN1 E280A ChLNs. The MC has therapeutic potential for treating early-onset FAD.

Protein Kinase C-Delta Mediates Cell Cycle Reentry and Apoptosis Induced by Amyloid-Beta Peptide in Post-Mitotic Cortical Neurons.

Amyloid-beta peptide (Aβ) is a neurotoxic constituent of senile plaques in the brains of Alzheimer's disease (AD) patients. The detailed mechanisms by which protein kinase C-delta (PKCδ) contributes to Aβ toxicity is not yet entirely understood. Using fully differentiated primary rat cortical neurons, we found that inhibition of Aβ25-35-induced PKCδ increased cell viability with restoration of neuronal morphology. Using cyclin D1, proliferating cell nuclear antigen (PCNA), and histone H3 phosphorylated at Ser-10 (p-Histone H3) as the respective markers for the G1-, S-, and G2/M-phases, PKCδ inhibition mitigated cell cycle reentry (CCR) and subsequent caspase-3 cleavage induced by both Aβ25-35 and Aβ1-42 in the post-mitotic cortical neurons. Upstream of PKCδ, signal transducers and activators of transcription (STAT)-3 mediated PKCδ induction, CCR, and caspase-3 cleavage upon Aβ exposure. Downstream of PKCδ, aberrant neuronal CCR was triggered by overactivating cyclin-dependent kinase-5 (CDK5) via calpain2-dependent p35 cleavage into p25. Finally, PKCδ and CDK5 also contributed to Aβ25-35 induction of p53-upregulated modulator of apoptosis (PUMA) in cortical neurons. Together, we demonstrated that, in the post-mitotic neurons exposed to Aβs, STAT3-dependent PKCδ expression triggers calpain2-mediated p35 cleavage into p25 to overactivate CDK5, thus leading to aberrant CCR, PUMA induction, caspase-3 cleavage, and ultimately apoptosis.

In 2024, the amyloid-cascade-hypothesis still remains a working hypothesis, no less but certainly no more.

The amyloid-cascade-hypothesis of the pathogenesis of Alzheimer's disease (AD) was introduced 32 years ago, in 1992. From early on, this clear and straight forward hypothesis received a lot of attention, but also a lot of substantial criticism. Foremost, there have always been massive doubts that a complex age-associated disorder of the most intricate organ of the human body, the brain, can be explained by a linear, one-dimensional cause-and-effect model. The amyloid-cascade defines the generation, aggregation, and deposition of the amyloid beta peptide as the central pathogenic mechanism in AD, as the ultimate trigger of the disease, and, consequently, as the key pharmacological target. Certainly, the original 1992 version of this hypothesis has been refined by various means, and the 'formulating fathers' followed up with a few reappraisals and partly very open reflections in 2002, 2006, 2009, and 2016. However, up until today, for the supporters of this hypothesis, the central and initial steps of the cascade are believed to be driven by amyloid beta-even if now displayed somewhat more elaborate. In light of the recently published clinical results achieved with anti-amyloid antibodies, the controversy in the field about (1) the clinical meaningfulness of this approach, (2) the significance of clearance of the amyloid beta peptide, and last but not least (3) the relevance of the amyloid-cascade-hypothesis is gaining momentum. This review addresses the interesting manifestation of the amyloid-cascade-hypothesis as well as its ups and downs over the decades.

The Effectiveness of Centella asiatica Extract and Aerobic Exercise on Plasma Levels of Amyloid Beta-42 and Phosphorylated Tau in Older Women with Dementia

Urgency: Effect of Centella asiatica (CA) and aerobic exercise on Amyloid beta-42 (Aβ42) and phosphorylated tau (p-tau) as biomarkers of dementia is not yet known. Objectives: This study aimed to analyze the effect of CA, aerobic exercise, and their combination on Aβ42 and p-tau in older women with dementia. Design: It was a 24-week randomized, double-blind controlled trial. Partisipants: Subjects were divided into four groups: the Centella asiatica group (CA, 1x500 mg/day, n = 16), the aerobic exercise group (AE, 3x60 minutes/week, n = 16), the CA-AE combination group (1x500 mg/day and exercise, n = 15), and the placebo group (n = 15). Instruments: The dementia screening test used the Mini Mental State Examination (Intraclass correlation coefficients : ranging from 0.60 to 0.93, sensitivity of 88.3%) and Clinical Dementia Rating questionnaires (sensitivity 93.6% and specificity 100%). The Wilcoxon, Kruskal-Wallis, and Mann-Whitney tests were used to analyze the data. Results: Plasma amyloid beta-42 showed an increase in all groups: CA (p

The amyloid beta 42/38 ratio as a plasma biomarker of early memory deficits in cognitively unimpaired older adults

The amyloid beta (Aβ) 42/40 ratio has been widely studied as a biomarker in Alzheimer’s disease (AD); however, other Aβ peptides could also represent relevant biomarkers. We measured levels of Aβ38/40/42 in plasma samples from cognitively-unimpaired older adults and determined the relationships between Aβ levels and amyloid positron-emission-tomography (PET) and performance on a learning and memory task. We found that all Aβ peptides individually and the Aβ42/40 ratio, but not the Aβ42/38 ratio, were significantly correlated with brain amyloid (Aβ-PET). Multiple linear modeling, adjusting for age, sex, education, APOE4 and Aβ-PET showed significant associations between the Aβ42/38 ratio and memory. Further, associations between the Aβ42/38 ratio and learning scores were stronger in males and in Aβ-PET-negative individuals. In contrast, no significant associations were detected between the Aβ42/40 ratio and any learning measure. These studies implicate the Aβ42/38 ratio as a biomarker to assess early memory deficits and underscore the utility of the Aβ38 fragment as an important biomarker in the AD field.

Association Between Type 2 Diabetes Mellitus and Alzheimer's Disease: Common Molecular Mechanism and Therapeutic Targets.

Diabetes mellitus (DM) and Alzheimer's disease (AD) rates are rising, mirroring the global trend of an aging population. Numerous epidemiological studies have shown that those with Type 2 diabetes (T2DM) have an increased risk of developing dementia. These degenerative and progressive diseases share some risk factors. To a large extent, the amyloid cascade is responsible for AD development. Neurofibrillary tangles induce neurodegeneration and brain atrophy; this chain reaction begins with hyperphosphorylation of tau proteins caused by progressive amyloid beta (Aβ) accumulation. In addition to these processes, it seems that alterations in brain glucose metabolism and insulin signalling lead to cell death and reduced synaptic plasticity in AD, before the onset of symptoms, which may be years away. Due to the substantial evidence linking insulin resistance in the brain with AD, researchers have coined the name "Type 3 diabetes" to characterize the condition. We still know little about the processes involved, even though current animal models have helped illuminate the links between T2DM and AD. This brief overview discusses insulin and IGF-1 signalling disorders and the primary molecular pathways that may connect them. The presence of GSK-3β in AD is intriguing. These proteins' association with T2DM and pancreatic β-cell failure suggests they might be therapeutic targets for both disorders.

Tyrosine phosphorylation and palmitoylation of TRPV2 ion channel tune microglial beta-amyloid peptide phagocytosis

Alzheimer’s disease (AD) is the leading form of dementia, characterized by the accumulation and aggregation of amyloid in brain. Transient receptor potential vanilloid 2 (TRPV2) is an ion channel involved in diverse physiopathological processes, including microglial phagocytosis. Previous studies suggested that cannabidiol (CBD), an activator of TRPV2, improves microglial amyloid-β (Aβ) phagocytosis by TRPV2 modulation. However, the molecular mechanism of TRPV2 in microglial Aβ phagocytosis remains unknown. In this study, we aimed to investigate the involvement of TRPV2 channel in microglial Aβ phagocytosis and the underlying mechanisms. Utilizing human datasets, mouse primary neuron and microglia cultures, and AD model mice, to evaluate TRPV2 expression and microglial Aβ phagocytosis in both in vivo and in vitro. TRPV2 was expressed in cortex, hippocampus, and microglia.Cannabidiol (CBD) could activate and sensitize TRPV2 channel. Short-term CBD (1 week) injection intraperitoneally (i.p.) reduced the expression of neuroinflammation and microglial phagocytic receptors, but long-term CBD (3 week) administration (i.p.) induced neuroinflammation and suppressed the expression of microglial phagocytic receptors in APP/PS1 mice. Furthermore, the hyper-sensitivity of TRPV2 channel was mediated by tyrosine phosphorylation at the molecular sites Tyr(338), Tyr(466), and Tyr(520) by protein tyrosine kinase JAK1, and these sites mutation reduced the microglial Aβ phagocytosis partially dependence on its localization. While TRPV2 was palmitoylated at Cys 277 site and blocking TRPV2 palmitoylation improved microglial Aβ phagocytosis. Moreover, it was demonstrated that TRPV2 palmitoylation was dynamically regulated by ZDHHC21. Overall, our findings elucidated the intricate interplay between TRPV2 channel regulated by tyrosine phosphorylation/dephosphorylation and cysteine palmitoylation/depalmitoylation, which had divergent effects on microglial Aβ phagocytosis. These findings provide valuable insights into the underlying mechanisms linking microglial phagocytosis and TRPV2 sensitivity, and offer potential therapeutic strategies for managing AD.

Cerebrovascular disease is associated with Alzheimer's plasma biomarker concentrations in adults with Down syndrome.

By age 40 years, over 90% of adults with Down syndrome have Alzheimer's disease pathology and most progress to dementia. Despite having few systemic vascular risk factors, individuals with Down syndrome have elevated cerebrovascular disease markers that track with the clinical progression of Alzheimer's disease, suggesting a role of cerebrovascular disease that is hypothesized to be mediated by inflammatory factors. This study examined the pathways through which small vessel cerebrovascular disease contributes to Alzheimer's disease-related pathophysiology and neurodegeneration in adults with Down syndrome. One hundred eighty-five participants from the Alzheimer's Biomarkers Consortium-Down Syndrome [mean (SD) age = 45.2 (9.3) years] with available MRI and plasma biomarker data were included in this study. White matter hyperintensity (WMH) volumes were derived from T2-weighted fluid-attenuated inversion recovery MRI scans, and plasma biomarker concentrations of amyloid beta 42/40, phosphorylated tau 217, astrocytosis (glial fibrillary acidic protein) and neurodegeneration (neurofilament light chain) were measured with ultrasensitive immunoassays. We examined the bivariate relationships of WMH, amyloid beta 42/40, phosphorylated tau 217 and glial fibrillary acidic protein with age-residualized neurofilament light chain across Alzheimer's disease diagnostic groups. A series of mediation and path analyses examined statistical pathways linking WMH and Alzheimer's disease pathophysiology to promote neurodegeneration in the total sample and groups stratified by clinical diagnosis. There was a direct and indirect bidirectional effect through the glial fibrillary acidic protein of WMH on phosphorylated tau 217 concentration, which was associated with neurofilament light chain concentration in the entire sample. Amongst cognitively stable participants, WMH was directly and indirectly, through glial fibrillary acidic protein, associated with phosphorylated tau 217 concentration, and in those with mild cognitive impairment, there was a direct effect of WMH on phosphorylated tau 217 and neurofilament light chain concentrations. There were no associations of WMH with biomarker concentrations among those diagnosed with dementia. The findings from this cross-sectional study suggest that among individuals with Down syndrome, cerebrovascular disease promotes neurodegeneration by increasing astrocytosis and tau pathophysiology in the presymptomatic phases of Alzheimer's disease, but future studies will need to confirm these associations with longitudinal data. This work joins an emerging literature that implicates cerebrovascular disease and its interface with neuroinflammation as a core pathological feature of Alzheimer's disease in adults with Down syndrome.

Axonal damage and inflammation response are biological correlates of decline in small-world values: a cohort study in autosomal dominant Alzheimer’s disease

Abstract The grey matter of the brain develops and declines in coordinated patterns during the lifespan. Such covariation patterns of grey matter structure can be quantified as grey matter networks, which can be measured with magnetic resonance imaging. In Alzheimer’s disease, the global organization of grey matter networks becomes more random, which is captured by a decline in the small-world coefficient. Such decline in the small-world value has been robustly associated with cognitive decline across clinical stages of Alzheimer’s disease. The biological mechanisms causing this decline in small-world values remain unknown. Cerebrospinal fluid (CSF) protein biomarkers are available for studying diverse pathological mechanisms in humans and can provide insight into decline. We investigated the relationships between 10 CSF proteins and small-world coefficient in mutation carriers (N = 219) and non-carriers (N = 136) of the Dominantly Inherited Alzheimer Network Observational study. Abnormalities in Amyloid beta, Tau, synaptic (Synaptosome associated protein-25, Neurogranin) and neuronal calcium-sensor protein (Visinin-like protein-1) preceded loss of small-world coefficient by several years, while increased levels in CSF markers for inflammation (Chitinase-3-like protein 1) and axonal injury (Neurofilament light) co-occurred with decreasing small-world values. This suggests that axonal loss and inflammation play a role in structural grey matter network changes.

Nanoscale Structural Characterization of Amyloid β 1-42 Oligomers and Fibrils Grown in the Presence of Fatty Acids.

Mono- and polyunsaturated fatty acids (FAs) are broadly used as food supplements. However, their effect on the aggregation of amyloidogenic proteins remains unclear. In this study, we investigated the effect of a large number of mono- and polyunsaturated, as well as fully saturated FAs on the aggregation of amyloid β1-42 (Aβ1-42) peptide. A progressive aggregation of this peptide is the expected molecular cause of Alzheimer's disease (AD), one of the most common neurodegenerative pathologies in the world. We found that arachidonic and stearic acids delayed the aggregation of Aβ1-42. Using Nano-Infrared spectroscopy, we found that FAs caused very little if any changes in the secondary structure of Aβ1-42 oligomers and fibrils formed at different stages of protein aggregation. However, the analyzed mono- and polyunsaturated, as well as fully saturated FAs uniquely altered the toxicity of Aβ1-42 fibrils. We found a direct relationship between the degree of FAs unsaturation and toxicity of Aβ1-42 fibrils formed in their presence. Specifically, with an increase in the degree of unsaturation, the toxicity Aβ1-42/FA fibrils increased. These results indicate that fully saturated or monounsaturated FAs could be used to decrease the toxicity of amyloid aggregates and, consequently, decelerate the development of AD.

Hop leaves: From waste to a valuable source of bioactive compounds – A multidisciplinary approach to investigating potential applications

After harvesting of cones used for beer production, the remaining hop vegetative biomass requires disposal. The hop plant contains bioactive compounds in all its parts—cones, leaves, and roots—exhibiting interesting antioxidant, antiviral, and antibacterial properties. In this work, extracts obtained from hop leaves, a plant material often neglected in the hop cultivation, have been investigated; the qualitative UHPLC-MS/MS and GC-TOF-MS characterization revealed the presence of bioactive compounds such as polyphenols, α- and β-acids and terpenes are present. The extract retained antioxidant activity, as verified by Folin-Ciocalteu, DPPH, ABTS and FRAP assays, and demonstrated some antimicrobial activity when combined with antibiotics, particularly against Gram-positive bacterial strains. Additionally, the extracts showed an ability to interact with proteins as human insulin, amyloid beta peptide, mucin and bovine serum albumin (BSA), has been detected, indicating their potential to counteract inflammatory processes and protect against Alzheimer's disease. These findings suggest that hop vegetative biomass, typically considered waste, can be potentially transformed into a valuable resource with applications in various fields, from nutraceuticals to pharmaceuticals and cosmetics, aligning with a circular economy perspective.

Abstract P233: Amyloid Beta Plaque Deposits Co-Localize with Endothelial Cells in the Hippocampus of Female APPswe/PSEN1dE9 Mice During the Onset of Amyloid Pathology

Increasing evidence shows that cardiovascular diseases are associated with an increased risk of cognitive impairment and Alzheimer’s diseases (AD). It is unknown whether systemic vascular dysfunction occurs prior to the development of AD, if this occurs in a sex-dependent manner, or whether endothelial cells play a role in the deposition of amyloid beta (Aβ) peptides. We hypothesized that female mice present with an exacerbated formation of Aβ peptides, and vascular dysfunction would occur during the onset of amyloid pathology, thus escalating its progression. To test this hypothesis, we used a double transgenic mouse model of early onset AD (APPswe/PSEN1dE9) prior to the onset of amyloid pathology (3 months of age) and during the onset of amyloid pathology (7 months of age). Immunofluorescence was performed in the hippocampus stained with Aβ 1-42 and CD31 antibodies. High resolution images were acquired on the confocal microscope. Acetylcholine-induced relaxation (1pM-30µM) was evaluated in mesenteric resistance arteries (MRA), and the data analyzed as non-linear curve regression and maximum effect (Emax). The statistical analysis was performed using Student’s t test, or two-way ANOVA followed by Tukey post-hoc ( p &lt;0.05*). We observed that during the onset of amyloid pathology (7-months-old), there was elevated Aβ deposition which co-localized with endothelial cells in the hippocampus from female but not male APP/PS1 mice [females colocalization rate (%): control 12.9 ± 2.0 vs . APP/PS1 25.1 ± 7.8, n=4; males colocalization rate (%): control 23.2 ± 6.5 vs. APP/PS1 15.3 ± 3.3, n=4]. In addition, the 7-month-old female APP/PS1 mice showed an exacerbated endothelium-dependent relaxation compared to the 3-month-old group (female APP/PS1 7-month-old ACh Emax: 97.1 ± 1.6*%, n=4 vs. 3-month-old ACh Emax: 70.1 ± 8.3%, n=6). Furthermore, endothelial dysfunction occurred prior to the onset of amyloid pathology irrespective of sex. Overall, these data showed that the endothelial dysfunction prior to the onset of amyloid pathology may be an early marker of AD. Further, a greater burden of Aβ formation in hippocampal endothelial cells from female but not male APP/PS1 mice may be associated with vascular abnormalities and dysfunction.