Ganoderic acid a decreased Aß42-induced neurotoxicity in PC12 cells by reduced mitochondrial damage.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder. Accumulation of ß-amyloid (Aß) in the brain has been recognized as a key factor in the onset and progression of Alzheimer's disease (AD).The accumulation of Aß in the brain catalyzes the production of reactive oxygen species (ROS), which in turn triggers oxidative damage to cellular components such as DNA, lipids, and proteins. In the present study, we investigated the protective effect of Ganoderic acid A (GA.A) against Aß42-induced apoptosis in PC12 cells. Changes in mitochondrial membrane potential indicated that GA.A treats mitochondrial dysfunction by decreasing Aß42 deposition and inhibiting neural protofiber tangle formation. Changes in intracellular Ca2+ and caspase-3 indicated that GA.A reduced mitochondrial damage by Aß42 in PC12 cells, thereby decreasing ROS accumulation and reducing Aß protofiber-induced cytotoxicity. These features suggest that GA.A has great potential as an effective neuroprotective drug in the treatment of Alzheimer's disease.

A Snake Venom Peptide and Its Derivatives Prevent Aß42 Aggregation and Eliminate Toxic Aß42 Aggregates In Vitro.

Over a century has passed since Alois Alzheimer first described Alzheimer's disease (AD), and since then, researchers have made significant strides in understanding its pathology. One key feature of AD is the presence of amyloid-ß (Aß) peptides, which form amyloid plaques, and therefore, it is a primary target for treatment studies. Naturally occurring peptides have garnered attention for their potential pharmacological benefits, particularly in the central nervous system. In this study, nine peptide derivatives of Crotamine, a polypeptide from Crotalus durissus terrificus Rattlesnake venom, as well as one d-enantiomer, were evaluated for their ability to modulate Aß42 aggregation through various assays such as ThT, QIAD, SPR, and sFIDA. All tested peptides were able to decrease Aß42 aggregation and eliminate Aß42 aggregates. Additionally, all of the peptides showed an affinity for Aß42. This study is the first to describe the potential of crotamine derivative peptides against Aß42 aggregation and to identify a promising d-peptide that could be used as an effective pharmacological tool against AD in the future.

Preparation and Characterization of Zn(II)-Stabilized Aß42 Oligomers.

Aß oligomers are being investigated as cytotoxic agents in Alzheimer's disease (AD). Because of their transient nature and conformational heterogeneity, the relationship between the structure and activity of these oligomers is still poorly understood. Hence, methods for stabilizing Aß oligomeric species relevant to AD are needed to uncover the structural determinants of their cytotoxicity. Here, we build on the observation that metal ions and metabolites have been shown to interact with Aß, influencing its aggregation and stabilizing its oligomeric species. We thus developed a method that uses zinc ions, Zn(II), to stabilize oligomers produced by the 42-residue form of Aß (Aß42), which is dysregulated in AD. These Aß42-Zn(II) oligomers are small in size, spanning the 10-30 nm range, stable at physiological temperature, and with a broad toxic profile in human neuroblastoma cells. These oligomers offer a tool to study the mechanisms of toxicity of Aß oligomers in cellular and animal AD models.

Understanding Aß Peptide Binding to Lipid Membranes: A Biophysical Perspective.

Aß peptides are known to bind neural plasma membranes in a process leading to the deposit of Aß-enriched plaques. These extracellular structures are characteristic of Alzheimer's disease, the major cause of late-age dementia. The mechanisms of Aß plaque formation and deposition are far from being understood. A vast number of studies in the literature describe the efforts to analyze those mechanisms using a variety of tools. The present review focuses on biophysical studies mostly carried out with model membranes or with computational tools. This review starts by describing basic physical aspects of lipid phases and commonly used model membranes (monolayers and bilayers). This is followed by a discussion of the biophysical techniques applied to these systems, mainly but not exclusively Langmuir monolayers, isothermal calorimetry, density-gradient ultracentrifugation, and molecular dynamics. The Methodological Section is followed by the core of the review, which includes a summary of important results obtained with each technique. The last section is devoted to an overall reflection and an effort to understand Aß-bilayer binding. Concepts such as Aß peptide membrane binding, adsorption, and insertion are defined and differentiated. The roles of membrane lipid order, nanodomain formation, and electrostatic forces in Aß-membrane interaction are separately identified and discussed.

The protective effects of Chromofungin in oligomeric amyloid ß42 (Aß42)-induced toxicity in neurons in Alzheimer's disease.

Oligomeric Aß42 is considered to play a harmful role in the pathophysiology of Alzheimer's disease (AD). Prolonged exposure to oligomeric Aß42 could induce neuronal damage including cellular senescence. Amelioration of Aß42-induced cellular senescence has been considered as a promising strategy for the treatment of AD. Chromofungin, a chromogranin A-derived peptide, has displayed various biological functions in different types of cells and tissues. However, the effects of Chromofungin on oligomeric Aß42-induced cellular senescence have not been previously reported. In the current study, we report a novel function of Chromofungin by showing that treatment with Chromofungin could ameliorate Aß42-induced neurotoxicity in M17 neuronal cells. The Cell Counting Kit-8 (CCK-8) assay and the lactate dehydrogenase (LDH) release experiments revealed that 0.5 and 1 mM are the optimal concentrations of Chromofungin for cell culture in M17 cells. Challenging with oligomeric Aß42 (5 µM) for 7 and 14 days led to a significant decrease in telomerase activity, which was rescued by Chromofungin dose-dependently. Additionally, the senescence-associated ß-galactosidase (SA-ß-gal) staining assay demonstrated that Chromofungin mitigated oligomeric Aß42-induced cellular senescence. Correspondingly, treatment with Chromofungin reversed the gene expression of human telomerase reverse transcriptase (hTERT), telomeric repeat-binding factor 2 (TERF2), and p21 against oligomeric Aß42 in M17 neurons. Interestingly, Chromofungin attenuated oligomeric Aß42-induced oxidative stress (OS) in M17 cells by reducing the production of intracellular reactive oxygen species (ROS) but increasing the levels of intracellular superoxide dismutase (SOD). Importantly, the presence of Chromofungin reduced the expression of cyclooxygenase2 (COX-2) as well as the generation of prostaglandin E2 (PGE2). Transduction with Ad-COX-2 impaired the effects of Chromofungin on telomerase activity and the profile of cellular senescence. Our findings suggest that Chromofungin might act as a potential agent for the treatment of AD.

Recalibrating the Risk-Benefit Profiles of Lecanemab and Donanemab: Scales, Immunoreactivity, and Changes in Amyloid-ß42.

Three recent anti-amyloid-ß antibody trials for Alzheimer's disease reported similar effect sizes, used non-reactive saline as placebo, and showed large numbers of adverse events including imaging anomalies (ARIA) that correlate with cognitive changes. Conversely, all previous antibody trials were less reactive and pronounced ineffective. We argue that these observations point to unblinding bias, inflating apparent efficacy and thus altering the risk-benefit balance. Further, we highlight data demonstrating that beyond reducing amyloid, monoclonal antibodies increase monomeric amyloid-ß42 in cerebrospinal fluid, which may explain potential benefits. We should recalibrate the efficacy of these antibodies and devote more resources into strategies beyond removing amyloid.

Inhibition of autophagosome-lysosome fusion contributes to TDCIPP-induced Aß1-42 production in N2a-APPswe cells.

Alzheimer's disease is the most common form of dementia and is characterized by cognitive impairment. The disruption of autophagosome-lysosome function has been linked to the pathogenesis of Alzheimer's disease. Tris (1,3-dichloro-2-propyl) phosphate (TDCIPP) is a widely used organophosphorus flame retardant that has the potential to cause neuronal damage. We found that TDCIPP significantly increased the expression of ß-site amyloid precursor protein (APP)-cleaving enzyme 1 (BACE1), presenilin-1 (PS1) and Aß42. Proteomic studies with TMT labeling revealed changes in the profiles of N2a-APPswe cells after exposure to TDCIPP. Proteomic and bioinformatics analyses revealed that lysosomal proteins were dysregulated in N2a-APPswe cells after treatment with TDCIPP. The LC3, P62, CTSD, and LAMP1 levels were increased after TDCIPP exposure, and dysregulated protein expression was validated by Western blotting. The exposure to TDCIPP led to the accumulation of autophagosomes, and this phenomenon was enhanced in the presence of chloroquine (CQ). Our results revealed for the first time that TDCIPP could be a potential environmental risk factor for AD development. The inhibition of autophagosome-lysosome fusion may have a significant impact on the generation of Aß1-42 in response to TDCIPP.

Safari with an Electron Gun: Visualization of Protein and Membrane Interactions in Mitochondria in Natural Environment.

This paper presents new structural data about mitochondria using correlative light and electron microscopy (CLEM) and cryo-electron tomography. These state-of-the-art structural biology methods allow studying biological objects at nanometer scales under natural conditions. Non-invasiveness of these methods makes them comparable to observing animals in their natural environment on a safari. The paper highlights two areas of research that can only be accomplished using these methods. The study visualized location of the Aß42 amyloid aggregates in relation to mitochondria to test a hypothesis of development of mitochondrial dysfunction in Alzheimer's disease. The results showed that the Aß42 aggregates do not interact with mitochondria, although some of them are closely located. Therefore, the study demonstrated that mitochondrial dysfunction is not directly associated with the effects of aggregates on mitochondrial structure. Other processes should be considered as sources of mitochondrial dysfunction. Second unique area presented in this work is high-resolution visualization of the mitochondrial membranes and proteins in them. Analysis of the cryo-ET data reveals toroidal holes in the lamellar structures of cardiac mitochondrial cristae, where ATP synthases are located. The study proposes a new mechanism for sorting and clustering protein complexes in the membrane based on topology. According to this suggestion, position of the OXPHOS system proteins in the membrane is determined by its curvature. High-resolution tomography expands and complements existing ideas about the structural and functional organization of mitochondria. This makes it possible to study the previously inaccessible structural interactions of proteins with each other and with membranes in vivo.

Ultrasensitive and Multiple Biomarker Discrimination for Alzheimer's Disease via Plasmonic & Microfluidic Sensing Technologies.

As the population ages, the worldwide prevalence of Alzheimer's disease (AD) as the most common dementia in the elderly is increasing dramatically. However, a long-term challenge is to achieve rapid and accurate early diagnosis of AD by detecting hallmarks such as amyloid beta (Aß42). Here, a multi-channel microfluidic-based plasmonic fiber-optic biosensing platform is established for simultaneous detection and differentiation of multiple AD biomarkers. The platform is based on a gold-coated, highly-tilted fiber Bragg grating (TFBG) and a custom-developed microfluidics. TFBG excites a high-density, narrow-cladding-mode spectral comb that overlaps with the broad absorption of surface plasmons for high-precision interrogation, enabling ultrasensitive monitoring of analytes. In situ detection and in-parallel discrimination of different forms of Aß42 in cerebrospinal fluid (CSF) are successfully demonstrated with a detection of limit in the range of ≈30-170 pg mL-1, which is one order of magnitude below the clinical cut-off level in AD onset, providing high detection sensitivity for early diagnosis of AD. The integration of the TFBG sensor with multi-channel microfluidics enables simultaneous detection of multiple biomarkers using sub-µL sample volumes, as well as combining initial binding rate and real-time response time to differentiate between multiple biomarkers in terms of binding kinetics. With the advantages of multi-parameter, low consumption, and highly sensitive detection, the sensor represents an urgently needed potentials for large-scale diagnosis of diseases at early stage.

An EWAS of dementia biomarkers and their associations with age, African ancestry, and PTSD.

BACKGROUND: Large-scale cohort and epidemiological studies suggest that PTSD confers risk for dementia in later life but the biological mechanisms underlying this association remain unknown. This study examined this question by assessing the influences of PTSD, APOE ε4 genotypes, DNA methylation, and other variables on the age- and dementia-associated biomarkers Aß40, Aß42, GFAP, NfL, and pTau-181 measured in plasma. Our primary hypothesis was that PTSD would be associated with elevated levels of these markers. METHODS: Analyses were based on data from a PTSD-enriched cohort of 849 individuals. We began by performing factor analyses of the biomarkers, the results of which identified a two-factor solution. Drawing from the ATN research framework, we termed the first factor, defined by Aß40 and Aß42, "Factor A" and the second factor, defined by GFAP, NfL and pTau-181, "Factor TN." Next, we performed epigenome-wide association analyses (EWAS) of the two-factor scores. Finally, using structural equation modeling (SEM), we evaluated (a) the influence of PTSD, age, APOE ε4 genotype and other covariates on levels of the ATN factors, and (b) tested the mediating influence of the EWAS-significant DNAm loci on these associations. RESULTS: The Factor A EWAS identified one significant locus, cg13053408, in FANCD2OS. The Factor TN analysis identified 3 EWAS-significant associations: cg26033520 near ASCC1, cg23156469 in FAM20B, and cg15356923 in FAM19A4. The SEM showed age to be related to both factors, more so with Factor TN (ß = 0.581, p < 0.001) than Factor A (ß = 0.330, p < 0.001). Genotype-determined African ancestry was associated with lower Factor A (ß = 0.196, p < 0.001). Contrary to our primary hypothesis, we found a modest negative bivariate correlation between PTSD and the TN factor scores (r = - 0.133, p < 0.001) attributable primarily to reduced levels of GFAP (r = - 0.128, p < 0.001). CONCLUSIONS: This study identified novel epigenetic associations with ATN biomarkers and demonstrated robust age and ancestral associations that will be essential to consider in future efforts to develop the clinical applications of these tests. The association between PTSD and reduced GFAP, which has been reported previously, warrants further investigation.

The Influence of Lipid Electric Charge on the Binding of Aß(1-42) Amyloid Peptide to Bilayers in the Liquid-Ordered State.

The amyloidogenic Aß peptides are widely considered as a pathogenic agent in Alzheimer's disease. Aß(1-42) would form aggregates of amyloid fibrils on the neuron plasma membranes, thus perturbing neuronal functionality. Conflicting data are available on the influence of bilayer order on Aß(1-42) binding to membranes. In the present study, a biophysical approach was used in which isothermal calorimetry and surface pressure measurements were applied to explore the interaction of Aß(1-42) in either monomeric, oligomeric, or fibrillar form with model membranes (bilayers or monolayers) in the liquid-ordered state that were either electrically neutral or negatively charged. In the latter case, this contained phosphatidic acid, cardiolipin, or ganglioside. The calorimetric studies showed that Aß(1-42) fibrils, oligomers, and monomers could bind and/or be inserted into bilayers, irrespective of electric charge, in the liquid-ordered state, except that monomers could not interact with electrically neutral bilayers. The monolayer studies in the Langmuir balance demonstrated that Aß(1-42) aggregation hindered peptide insertion into the monolayer, hindered insertion in the decreasing order of monomer > oligomer > fibril, and that lipid composition did not cause large differences in insertion, apart from a slight facilitation of monomer and oligomer insertion by gangliosides.

Freestanding Nanofiber-Assembled Aptasensor for Precisely and Ultrafast Electrochemical Detection of Alzheimer's Disease Biomarkers.

Amyloid beta-protein (AßAß) is a main hallmark of Alzheimer's disease (AD), and a low amount of Aß protein accumulation appears to be a potential marker for AD. Here, an electrochemical DNA biosensor based on polyamide/polyaniline carbon nanotubes (PA/PANI-CNTs) is developed with the aim of diagnosing AD early using a simple, low-cost, and accessible method to rapidly detect Aß42 in human blood. Electrospun PA nanofibers served as the skeleton for the successive in situ deposition of PANI and CNTs, which contribute both high conductivity and abundant binding sites for the Aß42 aptamers. After the aptamers are immobilized, this aptasensor exhibits precise and specific detection of Aß42 in human blood within only 4 min with an extremely fast response rate, lower detection limit, and excellent linear detection range. These findings make a significant contribution to advancing the development of serum-based detection techniques for Aß42, thereby paving the way for improved diagnostic capabilities in the field of AD.

APOE2 Heterozygosity Reduces Hippocampal Soluble Amyloid-ß42 Levels in Non-Hyperlipidemic Mice.

APOE2 lowers Alzheimer's disease (AD) risk; unfortunately, the mechanism remains poorly understood and the use of mice models is problematic as APOE2 homozygosity is associated with hyperlipidemia. In this study, we developed mice that are heterozygous for APOE2 and APOE3 or APOE4 and overexpress amyloid-ß peptide (Aß) (EFAD) to evaluate the effect of APOE2 dosage on Aß pathology. We found that heterozygous mice do not exhibit hyperlipidemia. Hippocampal but not cortical levels of soluble Aß42 followed the order E2/2FAD > E2/3FAD≤E3/3FAD and E2/2FAD > E2/4FAD < E4/4FAD without an effect on insoluble Aß42. These findings offer initial insights on the impact of APOE2 on Aß pathology.

A Chronic Increase in Blood-Brain Barrier Permeability Facilitates Intraneuronal Deposition of Exogenous Bloodborne Amyloid-Beta1-42 Peptide in the Brain and Leads to Alzheimer's Disease-Relevant Cognitive Changes in a Mouse Model.

Background: Increased blood-brain barrier (BBB) permeability and amyloid-ß (Aß) peptides (especially Aß1-42) (Aß42) have been linked to Alzheimer's disease (AD) pathogenesis, but the nature of their involvement in AD-related neuropathological changes leading to cognitive changes remains poorly understood. Objective: To test the hypothesis that chronic extravasation of bloodborne Aß42 peptide and brain-reactive autoantibodies and their entry into the brain parenchyma via a permeable BBB contribute to AD-related pathological changes and cognitive changes in a mouse model. Methods: The BBB was rendered chronically permeable through repeated injections of Pertussis toxin (PT), and soluble monomeric, fluorescein isothiocyanate (FITC)-labeled or unlabeled Aß42 was injected into the tail-vein of 10-month-old male CD1 mice at designated intervals spanning ∼3 months. Acquisition of learned behaviors and long-term retention were assessed via a battery of cognitive and behavioral tests and linked to neuropathological changes. Results: Mice injected with both PT and Aß42 demonstrated a preferential deficit in the capacity for long-term retention and an increased susceptibility to interference in selective attention compared to mice exposed to PT or saline only. Immunohistochemical analyses revealed increased BBB permeability and entry of bloodborne Aß42 and immunoglobulin G (IgG) into the brain parenchyma, selective neuronal binding of IgG and neuronal accumulation of Aß42 in animals injected with both PT and Aß42 compared to controls. Conclusion: Results highlight the potential synergistic role of BBB compromise and the influx of bloodborne Aß42 into the brain in both the initiation and progression of neuropathologic and cognitive changes associated with AD.

Dementia exacerbates periodontal bone loss in females.

BACKGROUND: Periodontitis is a chronic inflammatory disease defined by the pathologic loss of the periodontal ligament and alveolar bone in relation to aging. Although clinical cohort studies reported that periodontitis is significantly elevated in males compared to females, emerging evidence indicates that females with dementia are at a greater risk for periodontitis and decreased alveolar bone. OBJECTIVE: This study aimed to evaluate whether dementia is a potential sex-dependent risk factor for periodontal bone loss using an experimental model of periodontitis induced in the triple transgenic (3x-Tg) dementia-like mice and clinical samples collected from senior 65 plus age patients with diagnosed dementia. MATERIALS AND METHODS: We induced periodontitis in dementia-like triple-transgenic (3x-Tg) male and female mice and age-matched wild-type (WT) control mice by ligature placement. Then, alveolar bone loss and osteoclast activity were evaluated using micro-CT and in situ imaging assays. In addition, we performed dental examinations on patients with diagnosed dementia. Finally, dementia-associated Aß42 and p-Tau (T181) and osteoclastogenic receptor activator of nuclear factor kappa-Β ligand (RANKL) in gingival crevicular fluid (GCF) collected from mice and clinical samples were measured by enzyme-linked immunosorbent assay (ELISA). RESULTS: Alveolar bone loss and in situ osteoclast activity were significantly elevated in periodontal lesions of 3x-Tg females but not males, compared to wild-type control mice. In addition, we also observed that the probing pocket depth (PPD) was also significantly elevated in female patients with dementia. Using ELISA assay, we observed that females had elevated levels of osteoclastogenic RANKL and dementia-associated Aß42 and p-Tau (T181) in the GCF collected from experimental periodontitis lesions and clinical samples. CONCLUSION: Altogether, we demonstrate that females with dementia have an increased risk for periodontal bone loss compared to males.

The heritability of blood-based biomarkers related to risk of Alzheimer's disease in a population-based sample of early old-age men.

INTRODUCTION: Despite their increased application, the heritability of Alzheimer's disease (AD)-related blood-based biomarkers remains unexplored. METHODS: Plasma amyloid beta 40 (Aß40), Aß42, the Aß42/40 ratio, total tau (t-tau), and neurofilament light (NfL) data came from 1035 men 60 to 73 years of age (µ = 67.0, SD = 2.6). Twin models were used to calculate heritability and the genetic and environmental correlations between them. RESULTS: Additive genetics explained 44% to 52% of Aß42, Aß40, t-tau, and NfL. The Aß42/40 ratio was not heritable. Aß40 and Aß42 were genetically near identical (rg  = 0.94). Both Aß40 and Aß42 were genetically correlated with NfL (rg  = 0.35 to 0.38), but genetically unrelated to t-tau. DISCUSSION: Except for Aß42/40, plasma biomarkers are heritable. Aß40 and Aß42 share mostly the same genetic influences, whereas genetic influences on plasma t-tau and NfL are largely unique in early old-age men. The absence of genetic associations between the Aßs and t-tau is not consistent with the amyloid cascade hypothesis.

Association of APOE gene with longitudinal changes of CSF amyloid beta and tau levels in Alzheimer's disease: racial differences.

BACKGROUND: The Apolipoprotein E (APOE) ε4 allele is a risk factor for late-onset Alzheimer's disease (AD). However, no investigation has focused on racial differences in the longitudinal effect of APOE genotypes on CSF amyloid beta (Aß42) and tau levels in AD. METHODS: This study used data from the Alzheimer's Disease Neuroimaging Initiative (ADNI): 222 participants with AD, 264 with cognitive normal (CN), and 692 with mild cognitive impairment (MCI) at baseline and two years follow-up. We used a linear mixed model to investigate the effect of APOE-ε4-genotypes on longitudinal changes in the amyloid beta and tau levels. RESULTS: Individuals with 1 or 2 APOE ε4 alleles revealed significantly higher t-Tau and p-Tau, but lower amyloid beta Aß42 compared with individuals without APOE ε4 alleles. Significantly higher levels of log-t-Tau, log-p-Tau, and low levels of log-Aß42 were observed in the subjects with older age, being female, and the two diagnostic groups (AD and MCI). The higher p-Tau and Aß42 values are associated with poor Mini-Mental State Examination (MMSE) performance. Non-Hispanic Africa American (AA) and Hispanic participants were associated with decreased log-t-Tau levels (ß = - 0.154, p = 0.0112; ß = - 0.207, and p = 0.0016, respectively) as compared to those observed in Whites. Furthermore, Hispanic participants were associated with a decreased log-p-Tau level (ß = - 0.224, p = 0.0023) compared to those observed in Whites. There were no differences in Aß42 level for non-Hispanic AA and Hispanic participants compared with White participants. CONCLUSION: Our study, for the first time, showed that the APOE ε4 allele was associated with these biomarkers, however with differing degrees among racial groups.

Comparison of Neuroinflammation Induced by Hyperphosphorylated Tau Protein Versus Ab42 in Alzheimer's Disease.

Both neurofibrillary tangles and senile plaques are associated with inflammation in Alzheimer's disease (AD). Their relative degree of induced neuroinflammation, however, is not well established. Mouse models of AD that expressed either human Aß42 (n = 7) or human hyperphosphorylated tau protein alone (n = 3), wild type (n = 10), and human AD samples (n = 29 with 18 controls) were studied. The benefit of using mouse models that possess only human tau or amyloid-b is that it allows for the individual evaluation of how each protein affects neuroinflammation, something not possible in human tissue. Three indicators of neuroinflammation were examined: TLRs/RIG1 expression, the density of astrocytes and microglial cells, and well-established mediators of neuroinflammation (IL6, TNFα, IL1ß, and CXCL10). There was a statistically significant increase in neuroinflammation with all three variables in the mouse models with human tau only as compared to human Aß42 only or wild-type mice (each at p < 0.0001). Only the Aß42 5xFAD mice (n = 4) showed statistically higher neuroinflammation versus wild type (p = 0.0030). The human AD tissues were segregated into Aß42 only or hyperphosphorylated tau protein with Aß42. The latter areas showed increased neuroinflammation with each of the three variables compared to the areas with only Aß42. Of the TLRs and RIG-1, TLR8 was significantly elevated in both the mouse model and human AD and only in areas with the abnormal tau protein. It is concluded that although Aß42 and hyperphosphorylated tau protein can each induce inflammation, the latter protein is associated with a much stronger neuroinflammatory response vis-a-vis a significantly greater activated microglial response.

Intraneuronal ß-amyloid impaired mitochondrial proteostasis through the impact on LONP1.

Mitochondrial dysfunction plays a critical role in the pathogenesis of Alzheimer's disease (AD). Mitochondrial proteostasis regulated by chaperones and proteases in each compartment of mitochondria is critical for mitochondrial function, and it is suspected that mitochondrial proteostasis deficits may be involved in mitochondrial dysfunction in AD. In this study, we identified LONP1, an ATP-dependent protease in the matrix, as a top Aß42 interacting mitochondrial protein through an unbiased screening and found significantly decreased LONP1 expression and extensive mitochondrial proteostasis deficits in AD experimental models both in vitro and in vivo, as well as in the brain of AD patients. Impaired METTL3-m6A signaling contributed at least in part to Aß42-induced LONP1 reduction. Moreover, Aß42 interaction with LONP1 impaired the assembly and protease activity of LONP1 both in vitro and in vivo. Importantly, LONP1 knockdown caused mitochondrial proteostasis deficits and dysfunction in neurons, while restored expression of LONP1 in neurons expressing intracellular Aß and in the brain of CRND8 APP transgenic mice rescued Aß-induced mitochondrial deficits and cognitive deficits. These results demonstrated a critical role of LONP1 in disturbed mitochondrial proteostasis and mitochondrial dysfunction in AD and revealed a mechanism underlying intracellular Aß42-induced mitochondrial toxicity through its impact on LONP1 and mitochondrial proteostasis.

Alzheimer's Disease CSF Biomarkers as Possible Indicators of Tap-Test Response in Idiopathic Normal Pressure Hydrocephalus.

The aim of the present study is the evaluation of established Alzheimer's disease (AD) cerebrospinal fluid (CSF) biomarkers in patients with idiopathic normal-pressure hydrocephalus (iNPH), both individually and as a total profile, and the investigation of their use as potential predictors of Tap-test responsiveness. Fifty-three patients with iNPH participated in the study. Aß42, Aß40, total Tau and phospho-Tau proteins were measured in duplicate with double-sandwich ELISA assays. Clinical evaluation involved a 10 m timed walk test before an evacuative lumbar puncture (LP) and every 24 h for three consecutive days afterwards. Neuropsychological assessment involved a mini-mental state examination, frontal assessment battery, 5-word test and CLOX drawing test 1 and 2, which were also performed before and 48 h after LP. Response in the Tap-test was defined as a 20% improvement in gait and/or a 10% improvement in neuropsychological tests. The Aß42/Aß40 ratio was found to be significantly higher in Tap-test responders than non-responders. Total Tau and phospho-Tau CSF levels also differed significantly between these two groups, with Tap-test responders presenting with lower levels compared to non-responders. Regarding the AD CSF biomarker profile (decreased amyloid and increased Tau proteins levels), patients with a non-AD profile were more likely to have a positive response in the Tap-test than patients with an AD profile.