Cerebral Aβ Research Articles

Association of Midlife Depressive Symptoms with Regional Amyloid-β and Tau in the Framingham Heart Study.

Depressive symptoms predict increased risk for dementia decades before the emergence of cognitive symptoms. Studies in older adults provide preliminary evidence for an association between depressive symptoms and amyloid-β (Aβ) and tau accumulation. It is unknown if similar alterations are observed in midlife when preventive strategies may be most effective. The study aim was to evaluate the association between depressive symptoms and cerebral Aβ and tau in a predominately middle-aged cohort with examination of the apolipoprotein (APOE) ɛ4 allele as a moderator. Participants included 201 adults (mean age 53±8 years) who underwent 11C-Pittsburgh Compound B amyloid and 18F-Flortaucipir tau positron emission tomography (PET) imaging. Depressive symptoms were evaluated with the Center for Epidemiological Studies Depression Scale (CES-D) at the time of PET imaging, as well as eight years prior. Associations between depressive symptoms at both timepoints, as well as depression (CES-D≥16), with regional Aβ and tau PET retention were evaluated with linear regression adjusting for age and sex. Interactions with the APOE ɛ4 allele were explored. Depressive symptoms and depression were not associated with PET outcomes in the overall sample. However, among APOE ɛ4 allele carriers, there was a significant cross-sectional association between depressive symptoms and increased tau PET uptake in the entorhinal cortex (β= 0.446, SE = 0.155, p = 0.006) and amygdala (β= 0.350, SE = 0.133, p = 0.012). Although longitudinal studies are necessary, the results suggest that APOE ɛ4 carriers with depressive symptoms may present with higher susceptibility to early tau accumulation in regions integral to affective regulation and memory consolidation.

Gain of PITRM1 peptidase in cortical neurons affords protection of mitochondrial and synaptic function in an advanced age mouse model of Alzheimer's disease.

Mitochondrial dysfunction is one of the early pathological features of Alzheimer's disease (AD). Accumulation of cerebral and mitochondrial Aβ links to mitochondrial and synaptic toxicity. We have previously demonstrated the mechanism by which presequence peptidase (PITRM1)‐mediated clearance of mitochondrial Aβ contributes to mitochondrial and cerebral amyloid pathology and mitochondrial and synaptic stress in adult transgenic AD mice overexpressing Aβ up to 12 months old. Here, we investigate the effect of PITRM1 in an advanced age AD mouse model (up to 19–24 months) to address the fundamental unexplored question of whether restoration/gain of PITRM1 function protects against mitochondrial and synaptic dysfunction associated with Aβ accumulation and whether this protection is maintained even at later ages featuring profound amyloid pathology and synaptic failure. Using newly developed aged PITRM1/Aβ‐producing AD mice, we first uncovered reduction in PITRM1 expression in AD‐affected cortex of AD mice at 19–24 months of age. Increasing neuronal PITRM1 activity/expression re‐established mitochondrial respiration, suppressed reactive oxygen species, improved synaptic function, and reduced loss of synapses even at advanced ages (up to 19–24 months). Notably, loss of PITRM1 proteolytic activity resulted in Aβ accumulation and failure to rescue mitochondrial and synaptic function, suggesting that PITRM1 activity is required for the degradation and clearance of mitochondrial Aβ and Aβ deposition. These data indicate that augmenting PITRM1 function results in persistent life‐long protection against Aβ toxicity in an AD mouse model. Therefore, augmenting PITRM1 function may enhance Aβ clearance in mitochondria, thereby maintaining mitochondrial integrity and ultimately slowing the progression of AD.

Passive immunotherapy with a novel antibody against 3pE-modified Aβ demonstrates potential for enhanced efficacy and favorable safety in combination with BACE inhibitor treatment in plaque-depositing mice

The imbalance between production and clearance of amyloid β (Aβ) peptides and their resulting accumulation in the brain is an early and crucial step in the pathogenesis of Alzheimer's disease (AD). Therefore, Aβ is strongly positioned as a promising and extensively validated therapeutic target for AD. Investigational disease-modifying approaches aiming at reducing cerebral Aβ concentrations include prevention of de novo production of Aβ through inhibition of β-site amyloid precursor protein cleaving enzyme 1 (BACE1), and clearance of Aβ deposits via passive Aβ immunotherapy.We have developed a novel, high affinity antibody against Aβ peptides bearing a pyroglutamate residue at amino acid position 3 (3pE), an Aβ species abundantly present in plaque deposits in AD brains. Here, we describe the preclinical characterization of this antibody, and demonstrate a significant reduction in amyloid burden in the absence of microhemorrhages in different mouse models with established plaque deposition. Moreover, we combined antibody treatment with chronic BACE1 inhibitor treatment and demonstrate significant clearance of pre-existing amyloid deposits in transgenic mouse brain, without induction of microhemorrhages and other histopathological findings. Together, these data confirm significant potential for the 3pE-specific antibody to be developed as a passive immunotherapy approach that balances efficacy and safety. Moreover, our studies suggest further enhanced treatment efficacy and favorable safety after combination of the 3pE-specific antibody with BACE1 inhibitor treatment.

Role of Retinal Amyloid-β in Neurodegenerative Diseases: Overlapping Mechanisms and Emerging Clinical Applications.

Amyloid-β (Aβ) accumulations have been identified in the retina for neurodegeneration-associated disorders like Alzheimer’s disease (AD), glaucoma, and age-related macular degeneration (AMD). Elevated retinal Aβ levels were associated with progressive retinal neurodegeneration, elevated cerebral Aβ accumulation, and increased disease severity with a decline in cognition and vision. Retinal Aβ accumulation and its pathological effects were demonstrated to occur prior to irreversible neurodegeneration, which highlights its potential in early disease detection and intervention. Using the retina as a model of the brain, recent studies have focused on characterizing retinal Aβ to determine its applicability for population-based screening of AD, which warrants a further understanding of how Aβ manifests between these disorders. While current treatments directly targeting Aβ accumulations have had limited results, continued exploration of Aβ-associated pathological pathways may yield new therapeutic targets for preserving cognition and vision. Here, we provide a review on the role of retinal Aβ manifestations in these distinct neurodegeneration-associated disorders. We also discuss the recent applications of retinal Aβ for AD screening and current clinical trial outcomes for Aβ-associated treatment approaches. Lastly, we explore potential future therapeutic targets based on overlapping mechanisms of pathophysiology in AD, glaucoma, and AMD.

Mediators of cerebral hypoperfusion and blood-brain barrier leakiness in Alzheimer's disease, vascular dementia and mixed dementia.

In vascular dementia (VaD) and Alzheimer’s disease (AD), cerebral hypoperfusion and blood‐brain barrier (BBB) leakiness contribute to brain damage. In this study, we have measured biochemical markers and mediators of cerebral hypoperfusion and BBB in the frontal (BA6) and parietal (BA7) cortex and underlying white matter, to investigate the pathophysiology of vascular dysfunction in AD, VaD and mixed dementia. The ratio of myelin‐associated glycoprotein to proteolipid protein‐1 (MAG:PLP1), a post‐mortem biochemical indicator of the adequacy of ante‐mortem cerebral perfusion; the concentration of fibrinogen adjusted for haemoglobin level, a marker of blood‐brain barrier (BBB) leakiness; the level of vascular endothelial growth factor‐A (VEGF), a marker of tissue hypoxia; and endothelin‐1 (EDN1), a potent vasoconstrictor, were measured by ELISA in the frontal and parietal cortex and underlying white matter in 94 AD, 20 VaD, 33 mixed dementia cases and 58 age‐matched controls. All cases were assessed neuropathologically for small vessel disease (SVD), cerebral amyloid angiopathy (CAA) severity, Aβ and phospho‐tau parenchymal load, and Braak tangle stage. Aβ40 and Aβ42 were measured by ELISA in guanidine‐HCl tissue extracts. We found biochemical evidence of cerebral hypoperfusion in AD, VaD and mixed dementia to be associated with SVD, Aβ level, plaque load, EDN1 level and Braak tangle stage, and to be most widespread in mixed dementia. There was evidence of BBB leakiness in AD—limited to the cerebral cortex and related to EDN1 level. In conclusion, abnormalities of cerebral perfusion and BBB function in common types of dementia can largely be explained by a combination of arteriolosclerosis, and Aβ‐, tau‐ and endothelin‐related vascular dysfunction. The relative contributions of these processes vary considerably both between and within the diseases.

Association of Early β-Amyloid Accumulation and Neuroinflammation Measured With [11C]PBR28 in Elderly Individuals Without Dementia.

ObjectiveTo examine whether early β–amyloid (Aβ) accumulation and metabolic risk factors are associated with neuroinflammation in elderly individuals without dementia.MethodsWe examined 54 volunteers (mean age 70.0 years, 56% women, 51% APOE ɛ4 carriers) with the translocator protein (TSPO) tracer [11C]PBR28 to assess neuroinflammation and with [11C] Pittsburgh compound B (PiB) to assess cerebral Aβ accumulation. [11C]PBR28 and [11C]PiB standardized uptake value ratios (SUVRs) were quantified in 6 regions of interests by using the cerebellar cortex as a pseudo-reference and reference region, respectively. Fasting venous glucose, insulin, and high-sensitivity C-reactive protein (hs-CRP) values were determined. Homeostatic model assessment of insulin resistance (HOMA-IR) was calculated. A subset of individuals (n = 11) underwent CSF sampling, and Aβ40, Aβ42, total tau, phospho-tau, soluble TREM2, and YKL-40 levels were measured.ResultsAmong the whole study group, no significant association was found between [11C]PiB and [11C]PBR28 SUVR composite scores (slope 0.02, p = 0.30). However, higher [11C]PiB binding was associated with higher [11C]PBR28 binding among amyloid-negative ([11C]PiB composite score ≤1.5) (TSPO genotype–, age- and sex-adjusted slope 0.26, p = 0.008) but not among amyloid-positive (slope −0.004, p = 0.88) participants. Higher CSF soluble TREM2 (rs = 0.72, p = 0.01) and YKL-40 (rs = 0.63, p = 0.04) concentrations were associated with a higher [11C]PBR28 composite score. Higher body mass index, HOMA-IR, and hs-CRP were associated with higher [11C]PBR28 binding in brain regions where Aβ accumulation is first detected in Alzheimer disease.ConclusionsWhile there was no association between amyloid and neuroinflammation in the overall study group, neuroinflammation was associated with amyloid among the subgroup at early stages of amyloid pathology.

Assessment of the Effects of Altered Amyloid-Beta Clearance on Behavior following Repeat Closed-Head Brain Injury in Amyloid-Beta Precursor Protein Humanized Mice.

Traumatic brain injury (TBI) increases the risk for dementias including Alzheimer's disease (AD) and chronic traumatic encephalopathy. Further, both human and animal model data indicate that amyloid-beta (Aβ) peptide accumulation and its production machinery are upregulated by TBI. Considering the clear link between chronic Aβ elevation and AD as well as tau pathology, the role(s) of Aβ in TBI is of high importance. Endopeptidases, including the neprilysin (NEP)-like enzymes, are key mediators of Aβ clearance and may affect susceptibility to pathology post-TBI. Here, we use a "humanized" mouse model of Aβ production, which expresses normal human amyloid-beta precursor protein (APP) under its natural transcriptional regulation and exposed them to a more clinically relevant repeated closed-head TBI paradigm. These transgenic mice also were crossed with mice deficient for the Aβ degrading enzymes NEP or NEP2 to assess models of reduced cerebral Aβ clearance in our TBI model. Our results show that the presence of the human form of Aβ did not exacerbate motor (Rotarod) and spatial learning/memory deficits (Morris water maze) post-injuries, while potentially reduced anxiety (Open Field) was observed. NEP and NEP2 deficiency also did not exacerbate these deficits post-injuries and was associated with protection from motor (NEP and NEP2) and spatial learning/memory deficits (NEP only). These data suggest that normally regulated expression of wild-type human APP/Aβ does not contribute to deficits acutely after TBI and may be protective at this stage of injury.

Neuroprotective Effects of the FGF21 Analogue LY2405319.

To date, there are no effective treatments for Alzheimer's disease (AD). Thus, a significant need for research of therapies remains. One promising pharmacological target is the hormone fibroblast growth factor 21 (FGF21), which is thought to be neuroprotective. A clinical candidate for medical use could be the FGF21 analogue LY2405319 (LY), which has a specificity and potency comparable to FGF21. The present study investigated the potential neuroprotective effect of LY via PPARγ/apoE/abca1 pathway, which is known to degrade amyloid-β (Aβ) plaques by using primary glial cells and hippocampal organotypic brain slice cultures (OBSCs) from 30- and 50-week-old transgenic APPswe/PS1dE9 (tg) mice. By LY treatment of 52-week-old tg mice with advanced Aβ deposition, we further aimed to elaborate the effect of LY on AD pathology in vivo. LY application to primary glial cells caused an upregulation of pparγ, apoE, and abca1 mRNA expression and significantly decreased number and area of Aβ plaques in OBSCs. LY treatment in tg mice increased cerebral [18F] FDG uptake and N-acetylaspartate/creatine ratio indicating enhanced neuronal activity and integrity. Although LY did not reduce the number of Aβ plaques in tg mice, the number of iba1-positive cells was significantly decreased indicating reduced microgliosis. These data identified LY in vitro as an activator of Aβ degrading genes leading to cerebral Aβ load amelioration in early and late AD pathology. Although Aβ plaque reduction by LY failed in vivo, LY may be used as therapeutic agent to treat AD-related neuroinflammation and impaired neuronal integrity.

Increased choroidal thickness in adults with Down syndrome.

IntroductionPeople with Down syndrome (DS) are particularly susceptible to Alzheimer's disease (AD) due to the triplication of the amyloid precursor protein (APP) gene. In this cross‐sectional study, we hypothesized that choroidal thinning reported in sporadic AD (sAD) is mirrored in adults with DS.MethodsThe posterior pole of the eye for 24 adults with DS and 16 age‐matched controls (Ctrl) were imaged with optical coherence tomography. Choroidal thickness (ChT) was measured and analyzed in relation to cognitive status and cerebral amyloid beta (Aβ) load.ResultsChT was increased in people with DS (pwDS) compared to Ctrl. This increase was associated with gender differences and positively correlated with cerebral Aβ load in a small subset. There was no significant correlation detected between ChT and age or cognitive status.DiscussionIn contrast to sAD this study found a significantly thicker choroid in pwDS. Whether these changes are related to Aβ pathology in DS needs further investigation.

Impact of APOE‐ε4 on cerebral amyloid deposition in participants with abnormal soluble amyloid levels

AbstractBackgroundAmyloid pathology can be detected using cerebrospinal fluid (CSF) biomarkers and positron emission tomography (PET) imaging, even though they measure two distinct beta‐amyloid (Aβ) pools. While CSF Aβ concentrations reflect the clearance of soluble amyloid species from the brain, PET imaging informs on the presence of insoluble fibrillary plaques in the brain tissue. Many studies have shown the concordance between the two measures in individuals along the Alzheimer’s continuum. Here, we assessed whether APOE‐ε4, the major genetic risk factor for Alzheimer’s disease (AD), affects the pattern of cerebral Aβ load as a function of CSF Aβ levels.MethodThe first consecutive 276 cognitively unimpaired (CDR = 0) individuals of the ALFA+ study, aged between 48 and 74, with valid structural MRI and [18F]flutemetamol (FTM) PET, APOE genotyping and CSF samples were included. Aβ40 and Aβ42 concentrations were determined with the Roche NeuroToolKit (Roche Diagnostics) and parametric standardized uptake value ratio images (SUVr) were calculated with the whole cerebellum as reference region. A voxel‐wise regression was performed to predict FTM uptake, with the following independent variables: age, sex, APOE‐ε4, and CSF Aβ42/40 ratio. Statistical threshold was set to p < 0.001 with a cluster extent correction of 100 voxels.ResultAs expected, CSF Aβ42/40 ratio was negatively associated with cerebral FTM uptake (Figure 1a‐1b). Age and APOE‐ε4 gene dose mapped onto distinct spatial patterns of FTM‐binding across the whole sample (Figure 2b‐2c). Importantly, we found a significant interaction between CSF Aβ42/40 and APOE‐ε4 indicating that carriers had a negative association between fluid and imaging Aβ measures in the bilateral hippocampus, as well as the bilateral middle temporal and temporo‐parietal junction (Figure 3).ConclusionCompared to non‐carriers, APOE‐ε4 carriers showed higher cerebral Ab load for any given level of CSF Aβ42/40 in areas that are not typically vulnerable to Aβ deposition yet undergoing neurodegeneration early in the Alzheimer’s continuum, such as the hippocampus. This suggests that APOE‐ε4 may influence the biological mechanisms regulating the equilibrium between soluble and deposited amyloid, which may transcend the hindering effect caused by Aβ fibrillary plaques and render medial temporal lobe structures particularly vulnerable when Aβ metabolism becomes deficient.

Regional microstructural alteration of the corpus callosum in preclinical Alzheimer’s disease

AbstractBackgroundWhile previous studies consistently reported regional microstructural changes of the cerebral white matter (WM) in Alzheimer’s disease (AD) dementia and mild cognitive impairment (MCI), little information is available for such changes in the preclinical stage of AD. We first aimed to investigate regional microstructural alteration of the WM in cognitively normal (CN) older adults with amyloid‐beta (Aβ) deposition. We also tried to develop a prediction model for Aβ positivity in CN using information on WM microstructural alteration and clinical variables that can be easily obtained in memory clinics.MethodSeventy‐five CN older adults from the Korean Brain Aging Study for the Early diagnosis and prediction of Alzheimer’s disease (KBASE) cohort were included in the analyses. All Participants underwent comprehensive clinical and neuropsychological assessment, T1 MRI, diffusion tensor imaging (DTI), and [11C]PiB‐PET. All CN subjects were divided into Aβ positive (CN+) and negative (CN‐) based on the level of cerebral Aβ retention on [11C]PiB‐PET. Multivariate stepwise logistic regression analyses were conducted to develop Aβ positivity prediction models.ResultWhen compared to CN‐, CN+ showed high mean diffusivity (MD) value of the genu of the corpus callosum (CC_genu) (F(1,73) = 6.357, p = 0.014, Figure 1). The area under the curve (AUC) of the receiver operating characteristics curve for the Aβ positivity prediction model only using MD of the CC_genu was 0.653 [confidence interval (CI) = 0.511‐0.794]. Model with MD of the CC_genu, age, and word list recall and constructional recall test scores were finally selected. The AUC of the final model was 0.851 [CI = 0.765‐0.937] (Figure 2).ConclusionThe findings indicate that microstructural alteration of the CC_genu occurs even in the stage of preclinical AD. When taken together with episodic memory scores commonly available in clinical practice, information about such regional WM microstructural alteration can be used to screen preclinical AD.

Hypercholesterolemia accelerates Aβ deposition in regions associated with early amyloidosis

AbstractBackgroundHypercholesterolemia is a well‐established risk factor for developing Alzheimer's disease (AD). Mechanisms underlying this relationship, however, are still unclear. Recent experiments have reported conflicting findings regarding the relationship between amyloid‐beta (Aβ) and cholesterol. While in vitro studies have shown that cholesterol accelerates Aβ aggregation, an epidemiological investigation demonstrated that total serum cholesterol is not associated with Aβ load. Nevertheless, it is still unclear whether total serum cholesterol affects Aβ deposition in the human brain. Here, we aimed to assess whether high levels of total serum cholesterol are associated with the rate of Aβ aggregation in the brain. We hypothesized that high total serum cholesterol levels could accelerate cerebral amyloidosis of non‐demented subjects.MethodWe selected 207 non‐demented – cognitively unimpaired and mild cognitive impairment – participants from Alzheimer's Disease Neuroimaging Initiative (ADNI) who had available data for baseline cholesterol and longitudinal amyloid PET scans with [18F]AV45. Subjects were divided into two groups regarding their total serum cholesterol levels, being classified as normal (<200mg/dL; n=158) or abnormal (>200mg/dL; n=107). We performed a voxel‐wise general linear modelling to assess Aβ load differences between groups at baseline. Then, a longitudinal comparison was carried out to evaluate the rate of Aβ deposition in 4 years, calculated as "(IMAGE4_YEARS ‐ IMAGEBASELINE)x100/IMAGEBASELINE". Age, gender, APOEε4, cholesterol treatment and diagnostic group were used as covariates.ResultNo differences were found in Aβ load at baseline. By contrast, we observed a significantly higher rate of Aβ accumulation for the abnormal group in brain regions associated to early amyloidosis, including lateral temporal (peak t(200) = 4.498, p<0.0001) and parietal (peak t(200) = 4.504, p<0.0001) lobes, over a 4‐year period when compared to the normal group (Figure 1).ConclusionOur findings suggest that serum cholesterol dysmetabolism could influence cerebral Aβ aggregation. In addition, our analysis points to a potential communication between central and peripheral cholesterol compartments (perhaps intensified by hypercholesterolemia‐related inflammation). Also, it corroborates with the hypothesis that higher serum cholesterol levels accelerate the process of brain amyloidosis, stressing the need for further investigation on the mechanisms involved in this process.

Serum cortisol, cerebral amyloidosis, and neurodegeneration: A longitudinal study

AbstractBackgroundAlthough elevated blood cortisol has been repeatedly associated with Alzheimer`s disease (AD) and related cognitive decline, the pathological links underlying the association remain poorly understood. In this context, we aimed to investigate the relationship between serum cortisol and AD neuroimaging markers including amyloid beta protein (Aβ) deposition, tau deposition, AD‐signature region cerebral glucose metabolism (AD‐CM), AD‐signature region cortical thickness (AD‐CT), and adjusted hippocampal volume (HVa).MethodThis study was part of the of the Korean Brain Aging Study for Early Diagnosis and Prediction of Alzheimer’s Disease (KBASE), an ongoing prospective cohort study. A total of 503 middle‐aged and elderly adults, including cognitively normal adults and individuals with mild cognitive impairment and AD dementia, underwent comprehensive clinical and neuropsychological assessments, 11C‐Pittsburgh compound B (PiB)‐PET, 18F‐deoxyglucose (FDG)‐PET, MRI, and serum cortisol level quantification at baseline and 2 years later. A subset of subjects also received 18F‐AV‐1451 PET during the follow‐up evaluation.ResultAt baseline, a significant positive association was found between serum cortisol level and global cerebral Aβ deposition after controlling for the effects of potential confounders (i.e., age, sex, APOE4 status, cognitive status, vascular risk, and depression). In addition, cortisol level showed significant inverse association with AD‐CM even after controlling for global Aβ retention as well as the confounders. There was no significant relationship between cortisol and cerebral tau deposition. In regard of longitudinal changes of AD markers, baseline cortisol level also had significant positive association with increase of cerebral Aβ deposition over 2 years, but not with changes of any neurodegeneration markers.ConclusionThe findings indicate that high serum cortisol contribute to AD processes through pathological cerebral Aβ deposition. Additionally, cortisol appears to directly affect neurodegeneration in AD‐signature brain regions via Aβ‐independent mechanisms.

Induction of amyloid-\u03b2 deposits from serially transmitted, histologically silent, A\u03b2 seeds issued from human brains

In humans, iatrogenic transmission of cerebral amyloid-β (Aβ)-amyloidosis is suspected following inoculation of pituitary-derived hormones or dural grafts presumably contaminated with Aβ proteins as well as after cerebral surgeries. Experimentally, intracerebral inoculation of brain homogenate extracts containing misfolded Aβ can seed Aβ deposition in transgenic mouse models of amyloidosis or in non-human primates. The transmission of cerebral Aβ is governed by the host and by the inoculated samples. It is critical to better characterize the propensities of different hosts to develop Aβ deposition after contamination by an Aβ-positive sample as well as to better assess which biological samples can transmit this lesion. Aβ precursor protein (huAPPwt) mice express humanized non-mutated forms of Aβ precursor protein and do not spontaneously develop Aβ or amyloid deposits. We found that inoculation of Aβ-positive brain extracts from Alzheimer patients in these mice leads to a sparse Aβ deposition close to the alveus 18 months post-inoculation. However, it does not induce cortical or hippocampal Aβ deposition. Secondary inoculation of apparently amyloid deposit-free hippocampal extracts from these huAPPwt mice to APPswe/PS1dE9 mouse models of amyloidosis enhanced Aβ deposition in the alveus 9 months post-inoculation. This suggests that Aβ seeds issued from human brain samples can persist in furtive forms in brain tissues while maintaining their ability to foster Aβ deposition in receptive hosts that overexpress endogenous Aβ. This work emphasizes the need for high-level preventive measures, especially in the context of neurosurgery, to prevent the risk of iatrogenic transmission of Aβ lesions from samples with sparse amyloid markers.

Echinacoside Suppresses Amyloidogenesis and Modulates F-actin Remodeling by Targeting the ER Stress Sensor PERK in a Mouse Model of Alzheimer's Disease.

Endoplasmic reticulum stress (ERS) plays a vital and pathogenic role in the onset and progression of Alzheimer’s disease (AD). Phosphorylation of PKR-like endoplasmic reticulum kinase (PERK) induced by ERS depresses the interaction between actin-binding protein filamin-A (FLNA) and PERK, which promotes F-actin accumulation and reduces ER-plasma membrane (PM) communication. Echinacoside (ECH), a pharmacologically active component purified from Cistanche tubulosa, exhibits multiple neuroprotective activities, but the effects of ECH on ERS and F-actin remodeling remain elusive. Here, we found ECH could inhibit the phosphorylation of PERK. Firstly ECH can promote PERK-FLNA combination and modulate F-actin remodeling. Secondly, ECH dramatically decreased cerebral Aβ production and accumulation by inhibiting the translation of BACE1, and significantly ameliorated memory impairment in 2 × Tg-AD mice. Furthermore, ECH exhibited high affinity to either mouse PERK or human PERK. These findings provide novel insights into the neuroprotective actions of ECH against AD, indicating that ECH is a potential therapeutic agent for halting and preventing the progression of AD.

Exploring a Cost-Efficient Model for Predicting Cerebral Aβ Burden Using MRI and Neuropsychological Markers in the ADNI-2 Cohort.

Many studies have focused on the early detection of Alzheimer’s disease (AD). Cerebral amyloid beta (Aβ) is a hallmark of AD and can be observed in vivo via positron emission tomography imaging using an amyloid tracer or cerebrospinal fluid assessment. However, these methods are expensive. The current study aimed to identify and compare the ability of magnetic resonance imaging (MRI) markers and neuropsychological markers to predict cerebral Aβ status in an AD cohort using machine learning (ML) approaches. The prediction ability of candidate markers for cerebral Aβ status was examined by analyzing 724 participants from the ADNI-2 cohort. Demographic variables, structural MRI markers, and neuropsychological test scores were used as input in several ML algorithms to predict cerebral Aβ positivity. Out of five combinations of candidate markers, neuropsychological markers with demographics showed the most cost-efficient result. The selected model could distinguish abnormal levels of Aβ with a prediction ability of 0.85, which is the same as that for MRI-based models. In this study, we identified the prediction ability of MRI markers using ML approaches and showed that the neuropsychological model with demographics can predict Aβ positivity, suggesting a more cost-efficient method for detecting cerebral Aβ status compared to MRI markers.

Diagnostic performance and prediction of clinical progression of plasma phospho-tau181 in the Alzheimer's Disease Neuroimaging Initiative.

Whilst cerebrospinal fluid (CSF) and positron emission tomography (PET) biomarkers for amyloid-β (Aβ) and tau pathologies are accurate for the diagnosis of Alzheimer's disease (AD), their broad implementation in clinical and trial settings are restricted by high cost and limited accessibility. Plasma phosphorylated-tau181 (p-tau181) is a promising blood-based biomarker that is specific for AD, correlates with cerebral Aβ and tau pathology, and predicts future cognitive decline. In this study, we report the performance of p-tau181 in >1000 individuals from the Alzheimer's Disease Neuroimaging Initiative (ADNI), including cognitively unimpaired (CU), mild cognitive impairment (MCI) and AD dementia patients characterized by Aβ PET. We confirmed that plasma p-tau181 is increased at the preclinical stage of Alzheimer and further increases in MCI and AD dementia. Individuals clinically classified as AD dementia but having negative Aβ PET scans show little increase but plasma p-tau181 is increased if CSF Aβ has already changed prior to Aβ PET changes. Despite being a multicenter study, plasma p-tau181 demonstrated high diagnostic accuracy to identify AD dementia (AUC = 85.3%; 95% CI, 81.4-89.2%), as well as to distinguish between Aβ- and Aβ+ individuals along the Alzheimer's continuum (AUC = 76.9%; 95% CI, 74.0-79.8%). Higher baseline concentrations of plasma p-tau181 accurately predicted future dementia and performed comparably to the baseline prediction of CSF p-tau181. Longitudinal measurements of plasma p-tau181 revealed low intra-individual variability, which could be of potential benefit in disease-modifying trials seeking a measurable response to a therapeutic target. This study adds significant weight to the growing body of evidence in the use of plasma p-tau181 as a non-invasive diagnostic and prognostic tool for AD, regardless of clinical stage, which would be of great benefit in clinical practice and a large cost-saving in clinical trial recruitment.

Parallels between retinal and brain pathology and response to immunotherapy in old, late-stage Alzheimer's disease mouse models.

Despite growing evidence for the characteristic signs of Alzheimer's disease (AD) in the neurosensory retina, our understanding of retina–brain relationships, especially at advanced disease stages and in response to therapy, is lacking. In transgenic models of AD (APPSWE/PS1∆E9; ADtg mice), glatiramer acetate (GA) immunomodulation alleviates disease progression in pre‐ and early‐symptomatic disease stages. Here, we explored the link between retinal and cerebral AD‐related biomarkers, including response to GA immunization, in cohorts of old, late‐stage ADtg mice. This aged model is considered more clinically relevant to the age‐dependent disease. Levels of synaptotoxic amyloid β‐protein (Aβ)1–42, angiopathic Aβ1–40, non‐amyloidogenic Aβ1–38, and Aβ42/Aβ40 ratios tightly correlated between paired retinas derived from oculus sinister (OS) and oculus dexter (OD) eyes, and between left and right posterior brain hemispheres. We identified lateralization of Aβ burden, with one‐side dominance within paired retinal and brain tissues. Importantly, OS and OD retinal Aβ levels correlated with their cerebral counterparts, with stronger contralateral correlations and following GA immunization. Moreover, immunomodulation in old ADtg mice brought about reductions in cerebral vascular and parenchymal Aβ deposits, especially of large, dense‐core plaques, and alleviation of microgliosis and astrocytosis. Immunization further enhanced cerebral recruitment of peripheral myeloid cells and synaptic preservation. Mass spectrometry analysis identified new parallels in retino‐cerebral AD‐related pathology and response to GA immunization, including restoration of homeostatic glutamine synthetase expression. Overall, our results illustrate the viability of immunomodulation‐guided CNS repair in old AD model mice, while shedding light onto similar retino‐cerebral responses to intervention, providing incentives to explore retinal AD biomarkers.

Vesicular ATP-binding cassette transporters in human disease: relevant aspects of their organization for future drug development

Vesicular ATP-binding cassette transporters in human disease: relevant aspects of their organization for future drug development

Retinal Levels of Amyloid Beta Correlate with Cerebral Levels of Amyloid Beta in Young APPswe/PS1dE9 Transgenic Mice before Onset of Alzheimer’s Disease

Objectives Retina abnormalities are related to cognitive disorders in patients with Alzheimer's disease (AD). Retinal amyloid beta (Aβ) can be labeled by curcumin. We measured Aβ content in the cerebrum and retina of APPswe/PS1dE9 (APP) transgenic mice with early age to investigate the correlation between cerebrum and retina. Methods APP mice and age-matched wild-type mice were investigated every month from age 2 months to 6 months to assess changes in Aβ content in the retina and cerebrum. At the beginning of each month, mice were fed a curcumin diet (50 mg/kg/day) for 7 consecutive days. The Aβ levels in the retina and cerebrum were measured by ELISAs. Correlations were identified between retinal and cerebral Aβ contents using Pearson's correlation. Results In the absence of curcumin, there was a significant correlation between Aβ contents in the retina and cerebrum of APP mice (r = 0.7291, P = 0.0014). With increasing age, Aβ-mediated degenerative change in the cerebrum (P < 0.001 in 5 months) and retina (P < 0.01 in 5 months) increased significantly. The inhibitory effect of curcumin on the Aβ level was significant in the cerebrum (P < 0.001) and retina (P < 0.01) of older APP mice in the early stage of life. Conclusion We observed a significant correlation between the Aβ content in the retina and Aβ content in the cerebrum of APP mice. Our data suggest an appropriate time to measure retinal Aβ. Although curcumin can label Aβ in the retina, it also suppresses Aβ levels and weakens the degree of correlation between Aβ in cerebrum and retina tissues.