Pathological Features Of Alzheimer's Disease Research Articles

Curcumin effect on non-amyloidogenic pathway for preventing Alzheimer’s disease

Amyloid beta (Aβ) plaque deposition is a pathological feature of Alzheimer’s disease (AD) that is characterized by dementia. Therapies approaches affecting Aβ synthesis and accumulation are necessary for improving AD. The present review, as the future prospective study, focuses on the possible effect of curcumin on the non-amyloidogenic pathways for inhibiting the Aβ plaque in AD. Activators of non-amyloidogenic pathways emerge as a novel strategy in attenuating Aβ. Drugs and natural compounds can affect neurotrophic signaling pathways including protein kinase C (PKC), tyrosine kinase (TK), mitogen-activated protein kinase (MAPK)-extracellular signal-regulated kinase (ERK) signaling, and Ca2+ signaling as wells serotonergic and acetylcholine systems, resulting to stimulate nonamyloidogenic pathways. Curcumin, active constituent of Curcuma longa L. (turmeric), has a potent effect against AD through prevention Aβ generation and deposition. With attention to the effect of curcumin on the molecular mechanism behind the nonamyloidogenic pathways, we suggest designing more studies to identify curcumin as a therapeutic restricting AD agent via its impact on the non-amyloidogenic pathway.

Cellular Prion Protein as a Receptor of Toxic Amyloid-β42 Oligomers Is Important for Alzheimer's Disease.

The pathological features of Alzheimer’s disease (AD) include senile plaques induced by amyloid-β (Aβ) protein deposits, neurofibrillary tangles formed by aggregates of hyperphosphorylated tau proteins and neuronal cell loss in specific position within the brain. Recent observations have suggested the possibility of an association between AD and cellular prion protein (PrPC) levels. PrPC is a high affinity receptor for oligomeric Aβ and is important for Aβ-induced neurotoxicity and thus plays a critical role in AD pathogenesis. The determination of the relationship between PrPC and AD and the characterization of PrPC binding to Aβ will facilitate the development of novel therapies for AD.

Antiretroviral Drugs Promote Amyloidogenesis by De-Acidifying Endolysosomes.

Antiretroviral therapeutics (ART) have effectively increased the long-term survival of HIV-1 infected individuals. However, the prevalence of HIV-1 associated neurocognitive disorders (HAND) has increased and so too have clinical manifestations and pathological features of Alzheimer's disease (AD) in people living with HIV-1/AIDS. Although underlying mechanisms are not clear, chronic exposure to ART drugs has been implicated in the development of AD-like symptoms and pathology. ART drugs are categorized according to their mechanism of action in controlling HIV-1 levels. All ART drugs are organic compounds that can be classified as being either weak acids or weak bases, and these physicochemical properties may be of central importance to ART drug-induced AD-like pathology because weak bases accumulate in endolysosomes, weak bases can de-acidify endolysosomes where amyloidogenesis occurs, and endolysosome de-acidification increases amyloid beta (Aβ) protein production and decreases Aβ degradation. Here, we investigated the effects of ART drugs on endolysosome pH and Aβ levels in rat primary cultured neurons. ART drugs that de-acidified endolysosomes increased Aβ levels, whereas those that acidified endolysosomes decreased Aβ levels. Acidification of endolysosomes with the mucolipin transient receptor potential (TRPML) channel agonist ML-SA1 blocked ART drug-induced increases in Aβ levels. Further, ART drug-induced endolysosome de-acidification increased endolysosome sizes; effects that were blocked by ML-SA1-induced endolysosome acidification. These results suggest that ART drug-induced endolysosome de-acidification plays an important role in ART drug-induced amyloidogenesis and that endolysosome acidification might attenuate AD-like pathology in HIV-1 positive people taking ART drugs that de-acidify endolysosomes. Graphical Abstract.

ROLE OF ACUTE EXERCISE-INDUCED BRAIN BDNF ON APP PROCESSING AND BACE1

Perturbations in metabolism results in the accumulation of beta-amyloid, which is a pathological feature of Alzheimer's Disease (AD) (1). Beta-site amyloid precursor protein cleaving enzyme 1 (BACE1) is the rate limiting enzyme in the pathway responsible for beta-amyloid production (2). Exercise has been shown to reduce BACE1 activity, although the exact neurobiological mechanisms responsible are unknown (3). Exercise has also been shown to increase brain-derived neurotropic factor (BDNF) content and signaling (4), however whether this neurotrophic factor mediates the effects of exercise on BACE1 regulation requires further investigation. C57BL6 male mice were placed on a low (LFD; n=24) or high fat diet (HFD; n=24) for 10-weeks. Following the intervention, the mice either remained sedentary (n=12) or underwent an acute bout of treadmill running (n=12), proceeded by glucose/insulin tolerance tests and a Barnes maze test (spatial memory). Mice were euthanized and the prefrontal cortex was collected for protein quantification. Markers of the amyloidogenic pathway, along with targets of the BDNF signaling pathway, were examined. The 10-week HFD intervention led to increased body mass, inguinal and epididymal white adipose tissue mass, and liver mass (p < 0.05). HFD groups had impairments in glucose and insulin tolerance, as well as spatial memory (time in incorrect zones) (p < 0.05). A HFD led to increases in Akt phosphorylation (insulin signalling) and decreases in ERK phosphorylation (downstream of BDNF) (p < 0.05). An acute bout of exercise was able to recover ERK phosphorylation in the HFD group (p < 0.05) and significantly increase BDNF protein content in both LFD and HFD groups (p < 0.05). However, there were no changes in BACE1 protein content with diet or exercise (p > 0.05). Results from this study suggest that exercise can increase BDNF protein content in an obesogenic rodent model. Furthermore, a HFD potentially contributes to memory impairments by aberrant insulin signalling and impairments in BDNF signalling, which can be recovered through exercise. Although BACE1 protein content did not change, future analysis will examine BACE1 activity. Through these mechanisms, we gain further insight into using BDNF, mediated through exercise, as a therapeutic intervention.

Orobol: An Isoflavone Exhibiting Regulatory Multifunctionality against Four Pathological Features of Alzheimer's Disease.

We report orobol as a multifunctional isoflavone with the ability to (i) modulate the aggregation pathways of both metal-free and metal-bound amyloid-β, (ii) interact with metal ions, (iii) scavenge free radicals, and (iv) inhibit the activity of acetylcholinesterase. Such a framework with multifunctionality could be useful for developing chemical reagents to advance our understanding of multifaceted pathologies of neurodegenerative disorders, including Alzheimer's disease.

The First Generation of iPSC Line from a Korean Alzheimer's Disease Patient Carrying APP-V715M Mutation Exhibits a Distinct Mitochondrial Dysfunction.

Alzheimer's Disease (AD) is a progressive neurodegenerative disease, which is pathologically defined by the accumulation of amyloid plaques and hyper-phosphorylated tau aggregates in the brain. Mitochondrial dysfunction is also a prominent feature in AD, and the extracellular Aβ and phosphorylated tau result in the impaired mitochondrial dynamics. In this study, we generated an induced pluripotent stem cell (iPSC) line from an AD patient with amyloid precursor protein (APP) mutation (Val715Met; APP-V715M) for the first time. We demonstrated that both extracellular and intracellular levels of Aβ were dramatically increased in the APP-V715M iPSC-derived neurons. Furthermore, the APP-V715M iPSC-derived neurons exhibited high expression levels of phosphorylated tau (AT8), which was also detected in the soma and neurites by immunocytochemistry. We next investigated mitochondrial dynamics in the iPSC-derived neurons using Mito-tracker, which showed a significant decrease of anterograde and retrograde velocity in the APP-V715M iPSC-derived neurons. We also found that as the Aβ and tau pathology accumulates, fusion-related protein Mfn1 was decreased, whereas fission-related protein DRP1 was increased in the APP-V715M iPSC-derived neurons, compared with the control group. Taken together, we established the first iPSC line derived from an AD patient carrying APP-V715M mutation and showed that this iPSC-derived neurons exhibited typical AD pathological features, including a distinct mitochondrial dysfunction.

Examination of Alzheimer's disease by a combination of electrostatic force and mechanical measurement.

Alzheimer's disease (AD) is the most common dementia and neurodegenerative disorder disease in central nervous system, and threatens the people's health seriously. But till now there are no effective ways to diagnose and treat AD. Herein, the differences between charge propagation, surface morphology, and Young's modulus of the hippocampus, in healthy and AD mice have been investigated using advanced modes of Atomic Force Microscopy (AFM). The ability of charge transfer in AD samples has decreased compared with healthy samples. There are compact layered structures in hippocampus from healthy sample, whereas there are no obvious layered structures in hippocampus from AD sample. The Young's modulus of hippocampus from AD sample is about half of that from healthy sample. The results demonstrate that AFM will be helpful in the further study of the functions of hippocampus and pathogenyof AD. LAY DESCRIPTION: Alzheimer's disease is the most common cause of dementia, a neurodegenerative disease which especially affects elderly people, threatens people's health seriously. The pathological features of AD are senile plaques, neurofibrillary tangles, and cerebral atrophy. The main clinical symptoms of AD are progressive memory impairment, cognitive dysfunction, and loss of language skills, as there are disorder in limbic and cortices. The morbidity rate increases with age and is currently at 5% and 20% among people older than 65 and 85, respectively. Thus AD has a heavy socioeconomic burden, especially in an aging society. So far, there are no effective therapeutic clinical treatments, and no effective means and methods to test and diagnose early stage AD. This means that further studies are essential to gain a deeper, fundamental understanding of the pathogenesis of AD. In this work, the surface morphology, electrical and mechanical properties of the hippocampi from healthy and AD mice have been investigated by Atomic Force Microscopy (AFM) at nanometre scale for the first time. The hippocampi from healthy mice are composed of compact layered structures, whereas there are no obvious characteristic features in the hippocampi from AD mice. The electrical properties of hippocampus slices were studied by the Electrostatic Force Microscopy (EFM) mode of AFM. The charge propagation ability of axons from AD mice has decreased dramatically compared to that of healthy mice. After charge injection (injection voltage was +10 V) the charge density was 2.3 × 105 Cμm-2 in healthy samples, which was larger than that from the AD samples (1.0 × 105 Cμm-2 ). The Young's modulus of hippocampi from healthy and AD mice were 104.0 and 40.1 kPa, respectively, as revealed by the quantitative nanomechanical mapping (QNM) mode of AFM. It indicates that when AD occurs, the Young's modulus will be lower than the healthy sample. These observations and experimental approaches will be useful in future studies of the pathogeny of AD.

Diabetes Promotes Development of Alzheimer's Disease Through Suppression of Autophagy.

Recent studies suggest that diabetes predisposes patients to develop neurodegenerative Alzheimer's disease (AD), although the underlying mechanisms have yet to be determined. Compromised autophagy of neuronal cells, which occurs in the early stages of AD, has been shown to enhance disease progression. However, autophagic regulation as a mechanism connecting diabetes and AD has not been shown before. Here, we found that streptozotocin (STZ)-induced diabetic rats exhibited poorer performance on the social recognition test, Morris water maze, and plus-maze discriminative avoidance task, compared to PBS-treated normoglycemic control rats, likely resulting from increased brain deposition of amyloid-β peptide aggregates (Aβ) and increased phosphorylation of tau protein, two pathological features of AD. Moreover, diabetes-induced AD-like behavioral and pathological changes were associated with a decrease in neuronal cell autophagy. Furthermore, compromised cell autophagy was recapitulated in vitro in neuronal cells cultured in high glucose conditions. Thus, our data suggest that hyperglycemia in diabetes may directly inhibit neuronal cell autophagy, which subsequently enhances AD-associated pathological progression.

Cognitive Resilience to Alzheimer's Disease Pathology in the Human Brain.

Past research has focused on risk factors for developing dementia, with increasing recognition of "resilient" people who live to old age with intact cognitive function despite pathological features of Alzheimer's disease (AD). To evaluate demographic factors, mid-life characteristics, and non-AD neuropathology findings that may be associated with cognitive resilience to AD pathology. We analyzed data from 276 autopsy cases with intermediate or high levels of AD pathology from the Adult Changes in Thought study. We defined cognitive resilience as having Cognitive Abilities Screening Instrument scores ≥86 within two years of death and no clinical dementia diagnosis; non-resilient people had dementia diagnoses from AD or other causes before death. We compared mid-life characteristics, demographics, and additional neuropathology findings between resilient and non-resilient people. We used multivariable logistic regression to estimate odds ratios (ORs) with 95% confidence intervals (CIs) for being resilient compared to not being resilient adjusting for demographic and neuropathology factors. We classified 68 (25%) people as resilient and 208 (75%) as not resilient. A greater proportion of resilient people had a college degree (50%) compared with non-resilient (32%, p = 0.01). The odds of being resilient were significantly increased among people with a college education (OR = 2.01, 95% CI = 1.01-3.99) and significantly reduced among people with additional non-AD neuropathology findings such as hippocampal sclerosis (OR = 0.28, 95% CI = 0.09-0.89) and microinfarcts (OR = 0.34, 95% CI = 0.15-0.78). Increased education and absence of non-AD pathology may be independently associated with cognitive resilience, highlighting the importance of evaluating co-morbid factors in future research on mechanisms of cognitive resilience.

SMU‐A inhibits Aβ‐induced NLRP3 inflammasome via autophagy mediated by the AMPK/ULK1 and Raf/MEK/ERK pathways in microglia

Accumulation of β‐amyloid (Aβ) and its induced inflammation are recognized as two major pathological features of Alzheimer disease (AD). Autophagy, an intracellular catabolic mechanism, plays a pivotal role in neurodegenerative disease for degrading the toxic aggregated proteins such as Aβ, α‐Synuclein and mHtt. Recently, autophagy activation in microglia was reported to not only degrade extracellular Aβ fribils but also inhibit Aβ‐induced NLRP3 inflmmasome. In the present experiment, the potential autophagy inducers from SMU, a traditional Chinese medicine, were identified in microglial cells (BV‐2) by using column chromatography, UHPLC‐TOF/MS and NMR technologies. Total four ellagitannin flavonoids including SMU‐A, SMU‐B, SMU‐C and SMU‐D were identified, and SMU‐A was proved to possess the best autophagic effect in BV‐2 cells. Furthermore, the autophagy was activated through the AMPK/ULK1, Raf/MEK/ERK and ATG7 dependent, but independent of mTOR signaling pathway. In Aβ1‐42 induced BV‐2 cells, SMU‐A inhibits inflammasome containing NLRP3, ASC, IL‐1β and caspase1 via autophagy, which was reversed by the autophagic inhibitors such as compound C, SCH772984, hydroxychloroquine and SBI‐0206965. Additionally, SMU‐A can improve cell viability of PC12 induced injury by cell culture medium of Aβ‐induced BV‐2. Taken together, enhanced microglial autophagy is a promising new therapeutic strategy for AD, and demonstrate the autophagy inducers in SMU exerts the potential neuroprotective mechanism in suppressing neuroinflammatory responses by enhancing autophagy in microglial. Therefore, uncovering the components in SMU contributing to autophagy activation and its molecular mechanism provide new insight of PCP into novel therapies for the amelioration of AD.Support or Funding InformationThe Science and Technology Program of Luzhou” (grant numbers 2016LZXNYD‐T03 and 2017LZXNYD‐J28), “Educational Commission of Sichuan Province” (grant numbers 18ZA0528 and 18TD0051), “Science and Technology Planning Project of Sichuan Province” (grant numbers 2018JY0474 and 2018JY0237)This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Autophagy alleviates the decrease in proliferation of amyloid β1‑42‑treated bone marrow mesenchymal stem cells via the AKT/mTOR signaling pathway.

Alzheimer's disease (AD) and osteoporosis (OP) are 2 common progressive age-associated diseases, primarily affecting the elderly worldwide. Accumulating evidence has demonstrated that patients with AD are more likely to suffer from bone mass loss and even OP, but whether it is a pathological feature of AD or secondary to motor dysfunction remains poorly understood. The present study aimed to investigate whether amyloid-β1–42 (Aβ1–42), the typical pathological product of AD, exhibited a negative effect on the proliferation of bone marrow mesenchymal stem cells (BMSCs) and the role of autophagy. The proliferation of BMSCs was measured using a Cell Counting Kit-8 assay, cell cycle analysis and 5-ethynyl-2′-deoxyuridine (EdU) staining. The autophagy-associated proteins microtubule-associated proteins 1A/1B light chain 3B and sequestosome 1 (p62) were evaluated by western blot analysis and autophagosomes were detected by transmission electron microscopy and immunofluorescence. The activity of the protein kinase B (AKT)/mammalian target of rapamycin (mTOR) signaling pathway was measured using western blot analysis, and the autophagy inducer rapamycin (RAPA), inhibitor 3-methyladenine (3-MA) and the AKT activator SC79 were also used to investigate the role of AKT/mTOR signaling pathway and autophagy in the proliferation of BMSCs. The results suggested that the proliferation of BMSCs treated with Aβ1–42 was inhibited, with the autophagy level increasing following treatment with Aβ1–42 in a dose-dependent manner, while the AKT/mTOR signaling pathway participated in the regulation of the autophagy level. Activation of autophagy using RAPA inhibited the decrease in proliferation of BMSCs, while suppression of autophagy by 3-MA and activation of the AKT/mTOR signaling pathway increased the decrease in proliferation of BMSCs caused by Aβ1–42. It was concluded that Aβ1–42, as an external stimulus, suppressed the proliferation of BMSCs directly and that the AKT/mTOR signaling pathway participated in the regulation of the level of autophagy. Concomitantly, autophagy may serve as a resistance mechanism in inhibiting the decreased proliferation of BMSCs treated with Aβ1–42.

Multi-site dynamic recording for Aβ oligomers-induced Alzheimer's disease in vitro based on neuronal network chip

Alzheimer's disease (AD) is a chronic central neurodegenerative disease. The pathological features of AD are the extracellular deposition of senile plaques formed by amyloid-β oligomers (AβOs) and the intracellular accumulation of neurofibrillary tangles. However, due to the lack of effective method and experimental models to study the cognitive decline, communication at cell resolution and the implementation of interventions, the diagnosis and treatment on AD still progress slowly. In this paper, we established a pathological model of AD in vitro based on AβOs-induced hippocampal neuronal network chip for multi-site dynamic analysis of the neuronal electrical activity and network connection. The multiple characteristic parameters, including positive and negative spike intervals, firing rate and peak-to-peak values, were extracted through the analysis of spike signals, and two firing patterns from the interneurons and pyramidal neurons were recorded. The spatial firing patterns mapping and cross-correlation between channels were performed to validate the degeneration of neuronal network connectivity. Moreover, an electrical stimulation with frequency at 40 Hz was exerted to preliminarily explore the therapeutic effect on the pathological model of AD. This neuronal network chip enables the implementation of AD models in vitro for studying basic mechanisms of neurodegeneration within networks and for the parallel testing of various potential therapies. It can be a novel technique in the research of AD pathological model in vitro.

Low-dose pioglitazone can ameliorate learning and memory impairment in a mouse model of dementia by increasing LRP1 expression in the hippocampus

Amyloid-β (Aβ) accumulation in the brain is a pathological feature of Alzheimer’s disease (AD) and enhancing Aβ clearance is a potential therapeutic strategy. Pioglitazone is a peroxisome proliferator-activated receptor-γ (PPAR-γ) agonist and is widely used to treat type 2 diabetes. We previously reported that low-dose pioglitazone increased the expression of low-density lipoprotein receptor-related protein 1 (LRP1), which upregulates the clearance of Aβ, using human brain microvascular endothelial cells. We investigated whether low-dose pioglitazone can rescue the pathological phenotype and memory impairment in senescence-accelerated mouse prone-8 (SAMP8) mice by increasing LRP1 levels. SAMP8 mice were treated with vehicle or pioglitazone in dosages of 2 or 5 mg/kg/day for 7 weeks. In the water maze test, 2 mg/kg/day of pioglitazone significantly attenuated the increased escape latency in SAMP8 mice (p = 0.026), while 5 mg/kg/day of treatment did not. Compared with vehicle treatment, the hippocampi of SAMP8 mice with 2 mg/kg/day of pioglitazone exhibited fewer Aβ deposits and reduced Aβ1–40 levels, along with elevated LRP1 expression (p = 0.005). Collectively, our results proposed that a new therapeutic application of the PPAR-γ agonist for AD treatment should be considered at a lower dose than the conventional dose used to treat diabetes.

Asiatic Acid Attenuated Aluminum Chloride-Induced Tau Pathology, Oxidative Stress and Apoptosis Via AKT/GSK-3β Signaling Pathway in Wistar Rats.

Asiatic acid (AA), a triterpenoid present in Centella asiatica, possesses the ability to cross blood brain barrier and received considerable attention for its neuroprotective role. We have reported the benefit of AA against aluminum chloride (AlCl3)-induced amyloid pathology, enhanced acetylcholine esterase (AChE) activity, and inflammation in Alzheimer's disease (AD) like model rats. Based on that, to find the exact mechanism of action of AA, the present study was designed to evaluate the oxidative stress, tau pathology, apoptosis, and Akt/GSK3β signaling pathway on AlCl3-induced neurotoxicity in Wistar rats. AD-like pathology was induced by oral administration of AlCl3 (100mg/kg b.w.) for 6weeks, which demonstrated a significant reduction in spatial memory performance, anxiety, and motor dysfunction and diminished the expression of cyclin-dependent kinase 5 (CDK 5-enzyme implicated in the phosphorylation of tau proteins), pTau, oxidative stress, and apoptosis, whereas oral ingestion of AA (75mg/kg b.w.) for 7weeks attenuated the above-said indices, which could be by activating Akt/GSK3β pathway. Current results suggested that AA could be able to modulate various pathological features of AD and could hold promise in AD treatment.

Procyanidins and Alzheimer's Disease.

Procyanidins, the oligomeric compounds formed from catechin and epicatechin molecules, are potentially effective targets as nutraceuticals or pharmaceuticals in the prevention and treatment of Alzheimer's disease (AD). Natural procyanidins can attenuate AD pathological features, extracellular amyloid deposits, and neurofibrillary tangles via reducing Aβ accumulation and tau pathology. The enhancement of cognition as well as modulation of synaptic plasticity by these compounds also participated in the alleviation of AD. Notably, procyanidins and some of their metabolites have been observed to upregulate SIRT1 (silent information regulator 1) which is essential for normal cognitive and synaptic plasticity, and stimulate CREB (cAMP response element binding) which acts as a molecular switch from short- to long-term memory. Based on the interplay of CREB-SIRT1 axis, it is therefore conceivable that the regulation of procyanidins by the means of CREB-SIRT1 could promote the cognitive function and is thus conducive for AD pathogenesis. This review focuses on the role of procyanidins, the main group of flavonoids, on AD and the potential mechanism involved CREB-SIRT1 axis.

MiR-219-5p inhibits tau phosphorylation by targeting TTBK1 and GSK-3β in Alzheimer's disease.

As the most common neurodegenerative disease, Alzheimer's disease (AD) is characterized by memory, perception, and behavioral damage, which may ultimately lead to emotional fluctuation and even lethal delirium. Increasing studies indicate that microRNAs (miRNAs) are associated with pathological features of AD. However, the role of miR-219-5p in AD progression is still unclear. In this study, the functions of miR-219-5p were analyzed in vitro and in vivo. miR-219-5p was notably overexpressed in brain tissues of patients with AD. The overexpression of miR-219-5p activated the phosphorylation of Tau-Ser198, Tau-Ser199, Tau-Ser201, and Tau-Ser422. We further showed that miR-219-5p could mediate a decrease in the protein levels of tau-tubulin kinase 1 (TTBK1) and glycogen synthase kinase 3β (GSK-3β) by directly binding to their 3'-untranslated region, thereby promoting the phosphorylation of tau in SH-SY5Y Cells. Rescue experiments further revealed that the phosphorylation of tau-mediated by miR-219-5p was dependent on the inhibition of TTBK1 and GSK-3β. Moreover, suppressing the expression of both TTBK1 and GSK-3β using miR-219-5p remarkably rescued AD-like symptoms in amyloid precursor protein/presenilin 1 mice. Our findings indicate that the upregulation of TTBK1 and GSK-3β mediated by the loss of miR-219-5p is a possible mechanism that contributes to tau phosphorylation and AD progression.

ANTEMORTEM LONGITUDINAL MRI METRICS AS A BIOMARKER OF POSTMORTEM BRAAK NFT STAGING

The diagnosis of Alzheimer's disease (AD) can only be established through postmortem examination. The most widely used assessment method is “ABC staging”, involving the neuropathological gradation of diffuse amyloid plaques, neurofibrillary tangles (NFT), and neuritic plaques. NFT pathology is the strongest correlate of atrophy on structural magnetic resonance imaging (MRI) amongst all AD pathological features. Conversely, our goal was to identify regional MRI metrics for which longitudinal trajectories were the strongest predictors of postmortem neurofibrillary degeneration. We selected participants from three databases (ADNI, NACC and Rush Memory and Aging Project) providing up to 10 years of clinical and MRI longitudinal follow-up, as well as postmortem neuropathological data. After initial quality control, 104 subjects with at least two in vivo brain MRIs were retained, for a total of 402 scans. Bilateral surfaces, thicknesses and volumes from cortical and subcortical brain structures were extracted using FreeSurfer 5.3 (longitudinal processing pipeline). Yearly atrophy rates were then calculated for each of the resulting 232 measures. Nonparametric comparisons and correlation analyses using Kruskal-Wallis and Spearman's rank correlation tests were performed to screen for the best predictors of postmortem NFT staging as assessed by Braak score. There was a significant difference between Braak transentorhinal (I-II), limbic (III-IV) and isocortical (V-VI) stages for 75 radiological variables (p < .05). Most of these entities are part of the temporal lobe and ventricular system; were also present some limbic lobe structures such as the posterior cingulate cortex. When adjusted for multiple comparisons, only the annual atrophy rates of the left inferior temporal and right middle temporal volumes remained significantly different between Braak stages (p < .0002); these structures showed good correlations with the severity of NFT aggregation (-0.463 and -0.406, respectively). Trajectories of regional brain atrophy as detected by serial in vivo brain imaging reflect underlying severity and distribution of AD-associated neurofibrillary degeneration. In vivo MRI metrics may therefore be considered as a potential biomarker for the prediction of AD neuropathological staging in the living brain.

Brimapitide Reduced Neuronal Stress Markers and Cognitive Deficits in 5XFAD Transgenic Mice.

Alzheimer's disease (AD) is characterized by accumulations of amyloid-β (Aβ42) and hyperphosphorylated tau proteins, associated with neuroinflammation, synaptic loss, and neuronal death. Several studies indicate that c-Jun N-terminal kinase (JNK) is implicated in the pathological features of AD. We have investigated in 5XFAD mice, the therapeutic effects of Brimapitide, a JNK-specific inhibitory peptide previously tested with higher concentrations in another AD model (TgCRND8). Three-month-old 5XFAD and wild-type littermate mice were treated by intravenous injections of low doses (10 mg/kg) of Brimapitide every 3 weeks, for 3 or 6 months (n = 6-9 per group). Cognitive deficits and brain lesions were assessed using Y-maze, fear-conditioning test, and histological and biochemical methods. Chronic treatment of Brimapitide for 3 months resulted in a reduction of Aβ plaque burden in the cortex of 5XFAD treated mice. After 6 months of treatment, cognitive deficits were reduced but also a significant reduction of cell death markers and the pro-inflammatory IL-1β cytokine in treated mice were detected. The Aβ plaque burden was not anymore modified by the 6 months of treatment. In addition to modulating cognition and amyloid plaque accumulation, depending on the treatment duration, Brimapitide seems experimentally to reduce neuronal stress in 5XFAD mice.

CCAAT-Enhancer Binding Protein-beta (C/EBPP) Regulates Deltasecretase Expression, Mediating the Pathogenesis in Alzheimer's Disease

Delta-secretase, an age-dependent protease, cleaves both APP and Tau, mediating the formation of amyloid plaques and neurofibrillary tangle in Alzheimer's disease (AD). However, how aging contributes to an increase in delta-secretase expression and AD pathologies remains unclear. Here we show that a CCAAT-enhancer-binding protein (C/EBPβ), an inflammation-regulated transcription factor, acts as a key age-dependent effector elevating both delta-secretase (AEP) and inflammatory cytokines expression, mediating AD pathogenesis. We found that C/EBPβ dictates delta-secretase transcription and protein levels in an age-dependent manner. Notably, overexpression of C/EBPβ in young 3xTg mice strongly increases delta-secretase and accelerates the pathological features of AD, exacerbating cognitive dysfunctions, which is abolished by inactive AEP C189S. Conversely, depletion of C/EBPβ from old 3xTg or 5XFAD mice substantially diminishes delta-secretase and reduces AD pathologies, leading to amelioration of cognitive impairment in these AD mouse models. Thus, our findings support that C/EBPβ plays a pivotal role in AD pathogenesis presumably via increasing both delta-secretase expression and neuroinflammation.

Antidiabetic Polypill Improves Central Pathology and Cognitive Impairment in a Mixed Model of Alzheimer's Disease and Type 2 Diabetes.

Type 2 diabetes (T2D) is an important risk factor to suffer dementia, being Alzheimer's disease (AD) as the most common form. Both AD and T2D are closely related to aging and with a growing elderly population it might be of relevance to explore new therapeutic approaches that may slow or prevent central complications associated with metabolic disorders. Therefore, we propose the use of the antidiabetic polypill (PP), a pharmacological cocktail, commonly used by T2D patients that include metformin, aspirin, simvastatin, and an angiotensin-converting enzyme inhibitor. In order to test the effects of PP at the central level, we have long-term treated a new mixed model of AD-T2D, the APP/PS1xdb/db mouse. We have analyzed AD pathological features and the underlying specific characteristics that relate AD and T2D. As expected, metabolic alterations were ameliorated after PP treatment in diabetic mice, supporting a role for PP in maintaining pancreatic activity. At central level, PP reduced T2D-associated brain atrophy, showing both neuronal and synaptic preservation. Tau and amyloid pathologies were also reduced after PP treatment. Furthermore, we observed a reduction of spontaneous central bleeding and inflammation after PP treatment in diabetic mice. As consequence, learning and memory processes were improved after PP treatment in AD, T2D, and AD-T2D mice. Our data provide the basis to further analyze the role of PP, as an alternative or adjuvant, to slow down or delay the central complications associated with T2D and AD.