Amyloid-β Deposition Research Articles

Modulating the RAGE-Induced Inflammatory Response: Peptoids as RAGE Antagonists.

While the primary pathology of Alzheimer's disease (AD) is defined by brain deposition of amyloid-β (Aβ) plaques and tau neurofibrillary tangles, chronic inflammation has emerged as an important factor in AD etiology. Upregulated cell surface expression of the receptor for advanced glycation end-products (RAGE), a key receptor of innate immune response, is reported in AD. In parallel, RAGE ligands, including Aβ aggregates, HMGB1, and S100B, are elevated in AD brain. Activation of RAGE by these ligands triggers release of inflammatory cytokines and upregulates cell surface RAGE. Despite such observation, there are currently no therapeutics that target RAGE for treatment of AD-associated neuroinflammation. Peptoids, a novel class of potential AD therapeutics, display low toxicity, facile blood-brain barrier permeability, and resistance to proteolytic degradation. In the current study, peptoids were designed to mimic Aβ, a ligand that binds the V-domain of RAGE, and curtail RAGE inflammatory activation. We reveal the nanomolar binding capability of peptoids JPT1 and JPT1a to RAGE and demonstrate their ability to attenuate lipopolysaccharide-induced pro-inflammatory cytokine production as well as upregulation of RAGE cell surface expression. These results support RAGE antagonist peptoid-based mimics as a prospective therapeutic strategy to counter neuroinflammation in AD and other neurodegenerative diseases.

Ligustilide-loaded liposome ameliorates mitochondrial impairments and improves cognitive function via the PKA/AKAP1 signaling pathway in a mouse model of Alzheimer's disease.

Oxidative stress is an early event in the development of Alzheimer's disease (AD) and maybe a pivotal point of interaction governing AD pathogenesis; oxidative stress contributes to metabolism imbalance, protein misfolding, neuroinflammation and apoptosis. Excess reactive oxygen species (ROS) are a major contributor to oxidative stress. As vital sources of ROS, mitochondria are also the primary targets of ROS attack. Seeking effective avenues to reduce oxidative stress has attracted increasing attention for AD intervention. We developed liposome-packaged Ligustilide (LIG) and investigated its effects on mitochondrial function and AD-like pathology in the APPswe/PS1dE9 (APP/PS1) mouse model of AD, and analyzed possible mechanisms. We observed that LIG-loaded liposome (LIG-LPs) treatment reduced oxidative stress and β-amyloid (Aβ) deposition and mitigated cognitive impairment in APP/PS1 mice. LIG management alleviated the destruction of the inner structure in the hippocampal mitochondria and ameliorated the imbalance between mitochondrial fission and fusion in the APP/PS1 mouse brain. We showed that the decline in cAMP-dependent protein kinase A (PKA) and A-kinase anchor protein 1 for PKA (AKAP1) was associated with oxidative stress and AD-like pathology. We confirmed that LIG-mediated antioxidant properties and neuroprotection were involved in upregulating the PKA/AKAP1 signaling in APPswe cells in vitro. Liposome packaging for LIG is relatively biosafe and can overcome the instability of LIG. LIG alleviates mitochondrial dysfunctions and cognitive impairment via the PKA/AKAP1 signaling pathway. Our results provide experimental evidence that LIG-LPs may be a promising agent for AD therapy.

Tracking reactive astrogliosis in autosomal dominant and sporadic Alzheimer’s disease with multi-modal PET and plasma GFAP

BackgroundPlasma assays for the detection of Alzheimer’s disease neuropathological changes are receiving ever increasing interest. The concentration of plasma glial fibrillary acidic protein (GFAP) has been suggested as a potential marker of astrocytes or recently, amyloid-β burden, although this hypothesis remains unproven. We compared plasma GFAP levels with the astrocyte tracer 11C-Deuterium-L-Deprenyl (11C-DED) in a multi-modal PET design in participants with sporadic and Autosomal Dominant Alzheimer’s disease.MethodsTwenty-four individuals from families with known Autosomal Dominant Alzheimer’s Disease mutations (mutation carriers = 10; non-carriers = 14) and fifteen patients with sporadic Alzheimer’s disease were included. The individuals underwent PET imaging with 11C-DED, 11C-PIB and 18F-FDG, as markers of reactive astrogliosis, amyloid-β deposition, and glucose metabolism, respectively, and plasma sampling for measuring GFAP concentrations. Twenty-one participants from the Autosomal Dominant Alzheimer’s Disease group underwent follow-up plasma sampling and ten of these participants underwent follow-up PET imaging.ResultsIn mutation carriers, plasma GFAP levels and 11C-PIB binding increased, while 11C-DED binding and 18F-FDG uptake significantly decreased across the estimated years to symptom onset. Cross-sectionally, plasma GFAP demonstrated a negative correlation with 11C-DED binding in both mutation carriers and patients with sporadic disease. Plasma GFAP indicated cross-sectionally a significant positive correlation with 11C-PIB binding and a significant negative correlation with 18F-FDG in the whole sample. The longitudinal levels of 11C-DED binding showed a significant negative correlation with longitudinal plasma GFAP concentrations over the follow-up interval.ConclusionsPlasma GFAP concentration and astrocyte 11C-DED brain binding levels followed divergent trajectories and may reflect different underlying processes. The strong negative association between plasma GFAP and 11C-DED binding in Autosomal Dominant and sporadic Alzheimer’s disease brains may indicate that if both are markers of reactive astrogliosis, they may detect different states or subtypes of astrogliosis. Increased 11C-DED brain binding seems to be an earlier phenomenon in Alzheimer’s disease progression than increased plasma GFAP concentration.

Genetic Reduction of Insulin Signaling Mitigates Amyloid-β Deposition by Promoting Expression of Extracellular Matrix Proteins in the Brain.

The insulin/IGF-1 signaling (IIS) regulates a wide range of biological processes, including aging and lifespan, and has also been implicated in the pathogenesis of Alzheimer's disease (AD). We and others have reported that reduced signaling by genetic ablation of the molecules involved in IIS (e.g., insulin receptor substrate 2 [IRS-2]) markedly mitigates amyloid plaque formation in the brains of mouse models of AD, although the molecular underpinnings of the amelioration remain unsolved. Here, we revealed, by a transcriptomic analysis of the male murine cerebral cortices, that the expression of genes encoding extracellular matrix (ECM) was significantly upregulated by the loss of IRS-2. Insulin signaling activity negatively regulated the phosphorylation of Smad2 and Smad3 in the brain, and suppressed TGF-β/Smad-dependent expression of a subset of ECM genes in brain-derived cells. The ECM proteins inhibited Aβ fibril formation in vitro, and IRS-2 deficiency suppressed the aggregation process of Aβ in the brains of male APP transgenic mice as revealed by injection of aggregation seeds in vivo Our results propose a novel mechanism in AD pathophysiology whereby IIS modifies Aβ aggregation and amyloid pathology by altering the expression of ECM genes in the brain.SIGNIFICANCE STATEMENT The insulin/IGF-1 signaling (IIS) has been recognized as a regulator of aging, a leading risk factor for the onset of Alzheimer's disease (AD). In AD mouse models, genetic deletion of key IIS molecules markedly reduces the amyloid plaque formation in the brain, although the molecular underpinnings of this amelioration remain elusive. We found that the deficiency of insulin receptor substrate 2 leads to an increase in the expression of various extracellular matrices (ECMs) in the brain, potentially through TGF-β/Smad signaling. Furthermore, some of those ECMs exhibited the potential to inhibit amyloid plaque accumulation by disrupting the formation of Aβ fibrils. This study presents a novel mechanism by which IIS regulates Aβ accumulation, which may involve altered brain ECM expression.

Longitudinal trajectories of basal forebrain volume in normal aging and Alzheimer’s disease

Dysfunction of the cholinergic basal forebrain (BF) system and amyloid-β (Aβ) deposition are early pathological features in Alzheimer’s disease (AD). However, their association in early AD is not well-established. This study investigated the nature and magnitude of volume loss in the BF, over an extended period, in 516 older adults who completed Aβ-PET and serial magnetic resonance imaging scans. Individuals were grouped at baseline according to the presence of cognitive impairment (CU, CI) and Aβ status (Aβ−, Aβ+). Longitudinal volumetric changes in the BF and hippocampus were assessed across groups. The results indicated that high Aβ levels correlated with faster volume loss in the BF and hippocampus, and the effect of Aβ varied within BF subregions. Compared to CU Aβ+ individuals, Aβ-related loss among CI Aβ+ adults was much greater in the predominantly cholinergic subregion of Ch4p, whereas no difference was observed for the Ch1/Ch2 region. The findings support early and substantial vulnerability of the BF and further reveal distinctive degeneration of BF subregions during early AD.

The relationship between learning slopes and Alzheimer’s Disease biomarkers in cognitively unimpaired participants with and without subjective memory concerns

ABSTRACT Objective: Learning slopes represent serial acquisition of information during list-learning tasks. Although several calculations for learning slopes exist, the Learning Ratio (LR) has recently demonstrated the highest sensitivity toward changes in cognition and Alzheimer’s disease (AD) biomarkers. However, investigation of learning slopes in cognitively unimpaired individuals with subjective memory concerns (SMC) has been limited. The current study examines the association of learning slopes to SMC, and the role of SMC in the relationship between learning slopes and AD biomarkers in cognitively unimpaired individuals. Method: Data from 950 cognitively unimpaired participants from the Alzheimer’s Disease Neuroimaging Initiative (aged 55 to 89) were used to calculate learning slope metrics. Learning slopes among those with and without SMC were compared with demographic correction, and the relationships of learning slopes with AD biomarkers of bilateral hippocampal volume and β-amyloid pathology were determined. Results: Learning slopes were consistently predictive of hippocampal atrophy and β-amyloid deposition. Results were heightened for LR relative to the other learning slopes. Additionally, interaction analyses revealed different associations between learning slopes and hippocampal volume as a function of SMC status. Conclusions: Learning slopes appear to be sensitive to SMC and AD biomarkers, with SMC status influencing the relationship in cognitively unimpaired participants. These findings advance our knowledge of SMC, and suggest that LR – in particular – can be an important tool for the detection of AD pathology in both SMC and in AD clinical trials.

Irisin reduces amyloid-β by inducing the release of neprilysin from astrocytes following downregulation of ERK-STAT3 signaling

A pathological hallmark of Alzheimer's disease (AD) is the deposition of amyloid-β (Aβ) protein in the brain. Physical exercise has been shown to reduce Aβ burden in various AD mouse models, but the underlying mechanisms have not been elucidated. Irisin, an exercise-induced hormone, is the secreted form of fibronectin type-III-domain-containing 5 (FNDC5). Here, using a three-dimensional (3D) cell culture model of AD, we show that irisin significantly reduces Aβ pathology by increasing astrocytic release of the Aβ-degrading enzyme neprilysin (NEP). This is mediated by downregulation of ERK-STAT3 signaling. Finally, we show that integrin αV/β5 acts as the irisin receptor on astrocytes required for irisin-induced release of astrocytic NEP, leading to clearance of Aβ. Our findings reveal for the first time a cellular and molecular mechanism by which exercise-induced irisin attenuates Aβ pathology, suggesting a new target pathway for therapies aimed at the prevention and treatment of AD.

Tryptamine: A privileged scaffold for the management of Alzheimer's disease.

Alzheimer's disease (AD) is a chronic and irreversible neurodegenerative disease associated with aging. It is characterized by the progressive loss of memory and other cognitive functions. Although the exact etiology of AD is not well explored, several factors, such as the deposition of amyloid-β (Aβ) plaques, hyperphosphorylation of tau protein, presence of low levels of acetylcholine, and generation of oxidative stress, are key mediators in the progression of AD. Currently, the clinical treatment options for AD are limited and are based on cholinesterase (ChE) inhibitors (e.g., donepezil, rivastigmine, and galantamine), N-methyl-d-aspartic acid receptor antagonists (e.g., memantine), and the recently approved Aβ modulator (e.g., aducanumab). Tryptamine (2-(1H-indol-3-yl)ethan-1-amine) is a small molecule that contains an indole nucleus and an ethylamine side chain. It is also the active metabolite of tryptophan. It possesses a wide range of biological activities related to neurodegenerative disorders, such as ChE inhibition, Aβ aggregation inhibition, antioxidant effects, monoamine-oxidase inhibition, and neuroprotection. Several tryptamine-based hybrid analogs are currently being investigated as multifunctional agents for the development of novel hybrids for AD treatment. Thus, this review article aims to provide in-depth insights into the research progress and strategies for designing multifunctional agents used in Alzheimer's therapy.

CXCR6 orchestrates brain CD8+ T cell residency and limits mouse Alzheimer's disease pathology.

Neurodegenerative diseases, including Alzheimer's disease (AD), are characterized by innate immune-mediated inflammation, but functional and mechanistic effects of the adaptive immune system remain unclear. Here we identify brain-resident CD8+ T cells that coexpress CXCR6 and PD-1 and are in proximity to plaque-associated microglia in human and mouse AD brains. We also establish that CD8+ T cells restrict AD pathologies, including β-amyloid deposition and cognitive decline. Ligand-receptor interaction analysis identifies CXCL16-CXCR6 intercellular communication between microglia and CD8+ T cells. Further, Cxcr6 deficiency impairs accumulation, tissue residency programming and clonal expansion of brain PD-1+CD8+ T cells. Ablation of Cxcr6 or CD8+ T cells ultimately increases proinflammatory cytokine production from microglia, with CXCR6 orchestrating brain CD8+ T cell-microglia colocalization. Collectively, our study reveals protective roles for brain CD8+ T cells and CXCR6 in mouse AD pathogenesis and highlights that microenvironment-specific, intercellular communication orchestrates tissue homeostasis and protection from neuroinflammation.

Neuroprotective Effect of Saroglitazar on Scopolamine-Induced Alzheimer's in Rats: Insights into the Underlying Mechanisms.

Alzheimer's disease (AD) is one of the most prevalent and progressive neurodegenerative disorders, hallmarked by increased amyloid-β deposition and enhanced oxidative load in the brain, ensuing cognitive decline. The present study is aimed at elucidating the neuroprotective effect of saroglitazar, a dual peroxisome-proliferator-activated receptor (PPARα/γ) agonist used in the treatment of diabetic dyslipidemia, against memory impairment induced by intraperitoneal scopolamine injection. 30 male Wistar rats were randomly divided into the following five groups: (A) Veh + Veh, (B) SGZ + Veh, (C) Veh + SCOP, (D) DPZ + SCOP, and (E) SGZ + SCOP. Rats of the respective groups were pretreated with saroglitazar (10 mg/kg, p.o.) and donepezil (3 mg/kg, p.o.) once daily for 16 days. During the final 9 days of the study, a daily injection of scopolamine (3 mg/kg, i.p.) was administered to the respective groups. Adjacent to the scopolamine injection, behavioral tests such as the open field, Y maze, novel object recognition test, and Morris water maze were conducted to assess learning and memory. Additionally, biochemical parameters such as acetylcholinesterase (AChE), butyrylcholinesterase (BuChE), nitric oxide (NO), malondialdehyde (MDA), reduced glutathione (GSH), superoxide dismutase (SOD), brain-derived neurotrophic factor (BDNF), β-amyloid levels, and NF-κB were measured in the hippocampus. The rats that received scopolamine injections showed significantly impaired short-term spatial and learning memory. This was associated with an increase in β-amyloid, iNOS, nitric oxide (NO), malondialdehyde, NF-κB, and TNF-α levels in the hippocampus of AD rats. On the other hand, saroglitazar has provided promising data on its protective role in cognition by protecting the BDNF, SOD, and GSH decline. As a result, saroglitazar was found to be a promising therapy in AD by upregulating the antioxidant status and cholinergic activity and preventing memory loss. Collectively, findings in the present study revealed that saroglitazar protected AD by suppressing scopolamine-mediated learning and memory deficits, oxidative stress, and cholinergic damage. Studying these mechanisms may conclude the protective role of saroglitazar against AD. However, further studies in transgenic animals will provide numerous insights into treatment mechanisms and contribute to developing a therapeutic intervention for AD.

Hepatic soluble epoxide hydrolase: A promising target for unveiling the liver-brain axis in Alzheimer’s disease

Wu and Dong etal.1 report that hepatic soluble epoxide hydrolase (sEH) manipulation impacts amyloid-β (Aβ) deposits and cognitive impairment in mouse models for Alzheimer's disease (AD), suggesting that hepatic sEH activity is a promising therapeutic target to treat AD.

Abstract 106: Vascular Dysfunction In The Mesenteric Resistance Arteries Occurs Prior To The Occurrence Of Early-onset Alzheimer’S Disease In A Sex-dependent Manner

Alzheimer’s Disease (AD) and cardiovascular diseases (CVDs) are a major cause ofdisability and death among the older population. Familial Alzheimer’s Disease (FAD) islinked with an early onset AD (EOAD) pathology (<65years) that manifests throughpathogenic mutations in the presenilin (PSEN)1 and PSEN2 genes, leading to theincreased production of central amyloid β (Aβ) peptides. There is increasing evidencethat elevated blood pressure and peripheral arterial stiffness contribute to thedevelopment and increase the risk of β-amyloid deposition in the brain leading to cognitivedecline later in life. We hypothesized that peripheral vascular remodeling and vasculardysfunction in the aorta and mesenteric resistance arteries (MRA) would be observedprior to the development of EOAD. The MRA of male and female C57Bl/6J (control) andAD mice (B6. CApptm1DboTg(APPswe,PSEN1dE9)85Dbo) at 9-weeks-old were isolatedprior to the onset of AD. Acetylcholine-induced relaxation (1pM-30μM) andphenylephrine-induced contraction (0.1nM-30μM) were evaluated using wire myography.Pulse wave velocity (PWV) and H&E staining were used to measure vascular stiffnessand morphology, respectively. Data were analyzed as non-linear curve regression andmaximum response (Rmax) using the Student t test ( p <0.05*). MRA from AD miceshowed impaired relaxation in both males (Rmax: control 90±0.9 vs. AD 59±6.4* %, n=3-4) and females (Rmax: control 90±2.8 vs. AD 70±8.3*%, n=4-6). Interestingly,phenylephrine-induced contraction was reduced in arteries from males (Rmax: control11.7±0.9 vs . AD 7.7±0.8* mN, n=3-4), but not in arteries from females (Rmax: control9.3±1.3 vs. AD 8.1±0.6 mN, n=6-7). However, no differences were observed in the aortawall thickness in the male (control 51.8±2.9 vs. AD 72±9.2 μm, n=3-4), or female (control63.7±9.8 vs. AD 54±4.8μm, n=2-3) AD mice, as well as the PWV analysis from male ADmice (control 2.41±0.44 vs. AD 4.05±1.4 mm/ms, n=6). These data suggest that thechanges observed in the peripheral microvasculature prior to the onset of AD could laterhave direct effects on cerebral blood flow leading to areas of altered blood perfusion andmicrovascular damage, thus contributing to the genesis and maintenance of AD.

Advances in Amyloid-β Clearance in the Brain and Periphery: Implications for Neurodegenerative Diseases.

This review examines the role of impaired amyloid-β clearance in the accumulation of amyloid-β in the brain and the periphery, which is closely associated with Alzheimer's disease (AD) and cerebral amyloid angiopathy (CAA). The molecular mechanism underlying amyloid-β accumulation is largely unknown, but recent evidence suggests that impaired amyloid-β clearance plays a critical role in its accumulation. The review provides an overview of recent research and proposes strategies for efficient amyloid-β clearance in both the brain and periphery. The clearance of amyloid-β can occur through enzymatic or non-enzymatic pathways in the brain, including neuronal and glial cells, blood-brain barrier, interstitial fluid bulk flow, perivascular drainage, and cerebrospinal fluid absorption-mediated pathways. In the periphery, various mechanisms, including peripheral organs, immunomodulation/immune cells, enzymes, amyloid-β-binding proteins, and amyloid-β-binding cells, are involved in amyloid-β clearance. Although recent findings have shed light on amyloid-β clearance in both regions, opportunities remain in areas where limited data is available. Therefore, future strategies that enhance amyloid-β clearance in the brain and/or periphery, either through central or peripheral clearance approaches or in combination, are highly encouraged. These strategies will provide new insight into the disease pathogenesis at the molecular level and explore new targets for inhibiting amyloid-β deposition, which is central to the pathogenesis of sporadic AD (amyloid-β in parenchyma) and CAA (amyloid-β in blood vessels).

Hericium coralloides Ameliorates Alzheimer's Disease Pathologies and Cognitive Disorders by Activating Nrf2 Signaling and Regulating Gut Microbiota.

Alzheimer's disease (AD) is prone to onset and progression under oxidative stress conditions. Hericium coralloides (HC) is an edible medicinal fungus that contains various nutrients and possesses antioxidant properties. In the present study, the nutritional composition and neuroprotective effects of HC on APP/PS1 mice were examined. Behavioral experiments showed that HC improved cognitive dysfunction in APP/PS1 mice. Immunohistochemical and Western blotting results showed that HC reduced the levels of p-tau and amyloid-β deposition in the brain. By altering the composition of the gut microbiota, HC promoted the growth of short-chain fatty acid-producing bacteria and suppressed the growth of Helicobacter. Metabolomic results showed that HC decreased D-glutamic acid and oxidized glutathione levels. In addition, HC reduced the levels of reactive oxygen species, enhanced the secretion of superoxide dismutase, catalase, and glutathione peroxidase, inhibited the production of malondialdehyde and 4-hydroxynonenal, and activated the nuclear factor erythroid 2-related factor 2 (Nrf2) signaling pathway. Collectively, HC demonstrated antioxidant activity by activating Nrf2 signaling and regulating gut microbiota, further exerting neuroprotective effects. This study confirms that HC has the potential to be a clinically effective AD therapeutic agent and offers a theoretical justification for both the development and use of this fungus.

Cerebral Microbleed Patterns and Cortical Amyloid-β: The ARIC-PET Study.

Cerebral microbleeds (CMBs) are associated with cognitive decline, but their importance outside of cerebral amyloid angiopathy and the mechanisms of their impact on cognition are poorly understood. We evaluated the cross-sectional association between CMB patterns and cerebral Aβ (amyloid-β) deposition, by florbetapir positron emission tomography. The longitudinal ARIC study (Atherosclerosis Risk in Communities) recruited individuals from 4 US communities from 1987 to 1989. From 2012 to 2014, the ARIC-PET (Atherosclerosis Risk in Communities - Positron Emission Tomography) ancillary recruited 322 nondemented ARIC participants who completed 3T brain magnetic resonance imaging with T2*GRE as part of ARIC visit 5 to undergo florbetapir positron emission tomography imaging. Magnetic resonance imaging images were read for CMBs and superficial siderosis; on positron emission tomography, global cortical standardized uptake value ratio >1.2 was considered a positive Aβ scan. Multivariable logistic regression models evaluated CMB characteristics in association with Aβ positivity. Effect modification by sex, race, APOE status, and cognition was evaluated. CMBs were present in 24% of ARIC-PET participants. No significant associations were found between CMBs and Aβ positivity, but a pattern of isolated lobar CMBs or superficial siderosis was associated with over 4-fold higher odds of elevated Aβ when compared with those with no CMBs (odds ratio, 4.72 [95% CI, 1.16-19.16]). A similar elevated risk was not observed in those with isolated subcortical or mixed subcortical and either lobar CMBs or superficial siderosis. Although no significant interactions were found, effect estimates for elevated Aβ were nonsignificantly lower (P>0.10, odds ratio, 0.4-0.6) for a mixed CMB pattern, and odds ratios were nonsignificantly higher for lobar-only CMBs for 4 subgroups: women (versus men); Black participants (versus White participants), APOE ε4 noncarriers (versus carriers), and cognitively normal (versus mild cognitive impairment). In this community-based cohort of nondemented adults, lobar-only pattern of CMBs or superficial siderosis is most strongly associated with brain Aβ, with no elevated risk for a mixed CMB pattern. Further studies are needed to understand differences in CMB patterns and their meaning across subgroups.

Clinical Characteristics, Neuroimaging Markers, and Outcomes in Patients with Cerebral Amyloid Angiopathy: A Prospective Cohort Study.

Background and purpose: Sporadic cerebral amyloid angiopathy (CAA) is a small vessel disease, resulting from progressive amyloid-β deposition in the media/adventitia of cortical and leptomeningeal arterioles. We sought to assess the prevalence of baseline characteristics, clinical and radiological findings, as well as outcomes among patients with CAA, in the largest study to date conducted in Greece. Methods: Sixty-eight patients fulfilling the Boston Criteria v1.5 for probable/possible CAA were enrolled and followed for at least twelve months. Magnetic Resonance Imaging was used to assess specific neuroimaging markers. Data regarding cerebrospinal fluid biomarker profile and Apolipoprotein-E genotype were collected. Multiple logistic regression analyses were performed to identify predictors of clinical phenotypes. Cox-proportional hazard regression models were used to calculate associations with the risk of recurrent intracerebral hemorrhage (ICH). Results: Focal neurological deficits (75%), cognitive decline (57%), and transient focal neurological episodes (TFNEs; 21%) were the most common clinical manifestations. Hemorrhagic lesions, including lobar cerebral microbleeds (CMBs; 93%), cortical superficial siderosis (cSS; 48%), and lobar ICH (43%) were the most prevalent neuroimaging findings. cSS was independently associated with the likelihood of TFNEs at presentation (OR: 4.504, 95%CI:1.258-19.088), while multiple (>10) lobar CMBs were independently associated with cognitive decline at presentation (OR:5.418, 95%CI:1.316-28.497). cSS emerged as the only risk factor of recurrent ICH (HR:4.238, 95%CI:1.509-11.900) during a median follow-up of 20 months. Conclusions: cSS was independently associated with TFNEs at presentation and ICH recurrence at follow-up, while a higher burden of lobar CMBs with cognitive decline at baseline. These findings highlight the prognostic value of neuroimaging markers, which may influence clinical decision-making.

Design of Self-Assembled Nanoparticles as a Potent Inhibitor and Fluorescent Probe for β-Amyloid Fibrillization.

Alzheimer's disease (AD) remains incurable due to its complex pathogenesis. The deposition of β-amyloid (Aβ) in the brain appears much earlier than any clinical symptoms and plays an essential role in the occurrence and development of AD neuropathology, which implies the importance of early theranostics. Herein, we designed a self-assembled bifunctional nanoparticle (LC8-pCG-fLC8) for Aβ fluorescent diagnosis and inhibition. The nanoparticle was synthesized by click chemistry from Aβ-targeting peptide Ac-LVFFARKC-NH2 (LC8) and an Aβ fluorescent probe f with the zwitterionic copolymer poly(carboxybetaine methacrylate-glycidyl methacrylate) (p(CBMA-GMA), pCG). Owing to the high reactivity of epoxy groups, the peptide concentration of LC8-pCG-fLC8 nanoparticles reached about 4 times higher than that of the existing inhibitor LVFFARK@poly(carboxybetaine) (LK7@pCB). LC8-pCG-fLC8 exhibited remarkable inhibitory capability (suppression efficiency of 83.0% at 20 μM), altered the aggregation pathway of Aβ, and increased the survival rate of amyloid-induced cultured cells from 76.5% to 98.0% at 20 μM. Notably, LC8-pCG-fLC8 possessed excellent binding affinity, good biostability, and high fluorescence responsivity to β-sheet-rich Aβ oligomers and fibrils, which could be used for the early diagnosis of Aβ aggregation. More importantly, in vivo tests using transgenic C. elegans CL2006 stain showed that LC8-pCG-fLC8 could specifically image Aβ plaques, prolong the lifespan (from 13 to 17 days), and attenuate the AD-like symptoms (reducing paralysis and Aβ deposition). Therefore, self-assembled nanoparticles hold great potential in AD theranostics.

Modulation of aggregation and structural polymorphisms of β-amyloid fibrils in cellular environments by pyroglutamate-3 variant cross-seeding

Amyloidogenic deposition of β-amyloid (Aβ) peptides in human brain involves not only the wild-type Aβ (wt-Aβ) sequences, but also posttranslationally modified Aβ (PTM-Aβ) variants. Recent studies hypothesizes that the PTM-Aβ variants may trigger the deposition of wt-Aβ, which underlies the pathology of Sporadic Alzheimer's disease. Among PTM-Aβ variants, the pyroglutamate-3-Aβ (pyroE3-Aβ) has attracted much attention because of their significant abundances and broad distributions in senile plaques and dispersible and soluble oligomers. pyroE3-specific antibodies are being tested as potential anti-Aβ drugs in clinical trials. However, evidence that support the triggering effect of pyroE3-Aβ on wt-Aβ in cells remain lacking, which diminishes its pathological relevance. We show here that cross-seeding with pyroE3-Aβ40 leads to accelerated extracellular and intracellular aggregation of wt-Aβ40 in different neuronal cells. Cytotoxicity levels are elevated through the cross-seeded aggregation, comparing with the self-seeded aggregation of wt-Aβ40 or the static presence of pyroE3-Aβ40 seeds. For the extracellular deposition in mouse neuroblastoma Neuro2a (N2a) cells, the cytotoxicity elevation correlates positively with the seeding efficiency. Besides aggregation rates, cross-seeding with pyroE3-Aβ40 also modulates the molecular level structural polymorphisms of the resultant wt-Aβ40 fibrils. Using solid-state nuclear magnetic resonance (ssNMR) spectroscopy, we identified key structural differences between the parent pyroE3/ΔE3 and wt-Aβ40 fibrils within their fibrillar cores. Structural propagation from seeds to daughter fibrils is demonstrated to be more pronounced in the extracellular seeding in N2a cells by comparing the ssNMR spectra from different seeded wt-Aβ40 fibrils, but less significant in the intracellular seeding process in human neuroblastoma SH-SY5Y cells.

Cooperative effects of SIRT1 and SIRT2 on APP acetylation.

Alzheimer's disease (AD) is an age-related neurodegenerative disorder characterized by amyloid-β (Aβ) deposition and neurofibrillary tangles. Although the NAD+ -dependent deacetylases SIRT1 and SIRT2 play pivotal roles in age-related diseases, their cooperative effects in AD have not yet been elucidated. Here, we report that the SIRT2:SIRT1 ratio is elevated in the brains of aging mice and in the AD mouse models. In HT22 mouse hippocampal neuronal cells, Aβ challenge correlates with decreased SIRT1 expression, while SIRT2 expression is increased. Overexpression of SIRT1 prevents Aβ-induced neurotoxicity. We find that SIRT1 impedes SIRT2-mediated APP deacetylation by inhibiting the binding of SIRT2 to APP. Deletion of SIRT1 reduces APP recycling back to the cell surface and promotes APP transiting toward the endosome, thus contributing to the amyloidogenic processing of APP. Our findings define a mechanism for neuroprotection by SIRT1 through suppression of SIRT2 deacetylation, and provide a promising avenue for therapeutic intervention of AD.

Acute Myocardial Infarction and Risk of Cognitive Impairment and Dementia: A Review.

Cognitive impairment (CI) shares common cardiovascular risk factors with acute myocardial infarction (AMI), and is increasingly prevalent in our ageing population. Whilst AMI is associated with increased rates of CI, CI remains underreported and infrequently identified in patients with AMI. In this review, we discuss the evidence surrounding AMI and its links to dementia and CI, including pathophysiology, risk factors, management and interventions. Vascular dysregulation plays a major role in CI, with atherosclerosis, platelet activation, microinfarcts and perivascular inflammation resulting in neurovascular unit dysfunction, disordered homeostasis and a dysfunctional neurohormonal response. This subsequently affects perfusion pressure, resulting in enlarged periventricular spaces and hippocampal sclerosis. The increased platelet activation seen in coronary artery disease (CAD) can also result in inflammation and amyloid-β protein deposition which is associated with Alzheimer's Dementia. Post-AMI, reduced blood pressure and reduced left ventricular ejection fraction can cause chronic cerebral hypoperfusion, cerebral infarction and failure of normal circulatory autoregulatory mechanisms. Patients who undergo coronary revascularization (percutaneous coronary intervention or bypass surgery) are at increased risk for post-procedure cognitive impairment, though whether this is related to the intervention itself or underlying cardiovascular risk factors is debated. Mortality rates are higher in dementia patients with AMI, and post-AMI CI is more prevalent in the elderly and in patients with post-AMI heart failure. Medical management (antiplatelet, statin, renin-angiotensin system inhibitors, cardiac rehabilitation) can reduce the risk of post-AMI CI; however, beta-blockers may be associated with functional decline in patients with existing CI. The early identification of those with dementia or CI who present with AMI is important, as subsequent tailoring of management strategies can potentially improve outcomes as well as guide prognosis.