Alzheimer's Disease Process Research Articles

Cross‐Platform Synaptic Network Analysis of Alzheimer’s Disease Contextualizes Proteomic Targets for Functional Validation

AbstractBackgroundCognitive decline in Alzheimer’s disease (AD) correlates well with the extent of tau pathology and synapse or dendritic spine loss. Thus, studying synaptic processes may aid in the identification of new therapeutic targets that limit cognitive decline. The entorhinal cortex (EC) is an initial site of tau tangle formation, from which tau can propagate to other brain regions through synaptic connections. We developed a pipeline whereby dendritic spine density and morphology as well as synaptic tau measurements from the EC were incorporated into a synaptic proteomic network to identify mechanisms of synaptic pathology in AD patients.MethodGolgi‐stained dendrites from postmortem human BA28 EC were imaged using high‐resolution brightfield microscopy and digitally reconstructed in 3D for morphometric analysis. Synaptosome fractions were isolated from the same BA28 samples. Levels of synaptosome and insoluble phosphorylated tau were measured by ELISA. Additionally, liquid chromatography coupled with tandem mass spectrometry‐based proteomics was performed on synaptosomes. Weighted Gene Co‐Expression Network Analysis (WGCNA) was used to generate a synaptic network of protein co‐expression modules. Module expression was correlated with dendritic spine measurements and phospho‐tau levels to guide selection of proteins for validation in model systems. Validation experiments were performed in neurons and Neuro‐2a cells, using a CRISPR activation system for target gene upregulation.ResultSpine density in the EC is reduced in AD, but not in cognitively normal individuals with AD pathology (CAD) cases. AD cases exhibit more synaptosomal pS396 tau than CAD cases. Module expression was correlated with dendritic spine density and morphology. We identified TWF2 as a hub protein of Module 16, which is positively correlated with thin spine length. Twf2 upregulation increased thin spine length in cultured neurons. Module expression was then correlated with phospho‐tau levels. We identified PPP1R7 as a hub protein of Module 24, which is inversely correlated with synaptosomal pS396 tau in human EC.ConclusionWe demonstrate that incorporating orthogonal cellular and molecular measurements into a proteomic network enables unbiased identification of proteins functionally involved in regulating those traits. Beyond elucidating synaptic processes in AD, this pipeline offers a blueprint to better contextualize omics‐based targets with relevant biological mechanisms.

Evaluating the biological variability of blood‐based biomarkers for use in clinical trials

AbstractBackgroundBlood‐based biomarkers offer the possibility of inexpensive, minimally invasive, and accessible diagnostic tools for Alzheimer’s Disease (AD). In the context of clinical trials, these biomarkers hold promise for subject stratification and monitoring the effects of therapeutic interventions. The day‐to‐day variability of these measures must be robustly characterized to determine which blood‐based biomarkers would be the most sensitive for detecting treatment‐related responses. In this study we evaluate biomarker performance in plasma and identify the most reliable candidates for clinical trials.MethodEDTA plasma samples were collected from healthy controls (n=20, 50% female, mean age 56.03 ± 9.43 years) at baseline, 2 weeks, and 4 weeks. Singleplex ELISA and multiplex MesoScale Discovery (MSD) immunoassays were used to measure over 25 biomarkers that were selected for their relevance to dysregulated processes in AD and previously validated in cerebrospinal fluid (CSF). Technical performance was assessed by calculating intra‐ and inter‐plate coefficients of variation (CVs), analyzing dilution linearity, and evaluating freeze‐thaw stability. Biological intra‐individual variability was examined by calculating a biotemporal CV for each subject across the three timepoints.ResultsMost biomarkers were quantifiable in plasma and exhibited technical performance within our thresholds (intra‐ and inter‐plate CV < 15%). The biomarkers exhibited a range of freeze‐thaw stability, with mean CVs from 5.2% for Adiponectin, a regulator of glucose metabolism, to 30.2% for GRP78, an ER chaperone protein. Plasma levels were relatively stable across time (biotemporal CV < 20%) for several biomarkers, including 24‐OHC, VEGF‐D, Flt‐1, PlGF, sST2, and sTREM2. Several proteins exhibited significant variability over time (biotemporal CV > 20%), such as 8‐OHdG, GRP78, and YKL‐40.ConclusionKey metabolic, vascular, and inflammatory biomarkers were reliably measurable in the plasma of healthy individuals. Several markers exhibited substantial variability over a 2‐4 week time period, which should be taken into consideration when selecting appropriate markers for assessing drug‐target engagement. Designing future clinical trials with multiple baseline visits will allow us to establish biological variability metrics for each individual’s biomarker levels, providing greater confidence in determining treatment effects. Evaluating biomarker stability in other large‐scale subject populations will be necessary to best inform blood‐based biomarker selection for clinical trials.

Explicabilité en Intelligence Artificielle ; vers une IA Responsable - Instanciation dans le domaine de la santé

Quantifying the distribution and morphology of tau protein structures in brain tissues is key to diagnosing Alzheimer's Disease (AD) and its subtypes. Recently, deep learning (DL) models such as UNet have been successfully used for automatic segmentation of histopathological whole slide images (WSI) of biological tissues. In this study, we propose a DL-based methodology for semantic segmentation of tau lesions (i.e., neuritic plaques) in WSI of postmortem patients with AD. The state of the art in semantic segmentation of neuritic plaques in human WSI is very limited. Our study proposes a baseline able to generate a significant advantage for morphological analysis of these tauopathies for further stratification of AD patients. Essential discussions concerning biomarkers (ALZ50 versus AT8 tau antibodies), the imaging modality (different slide scanner resolutions), and the challenge of weak annotations are addressed within this seminal study. The analysis of the impact of context in plaque segmentation is important to understand the role of the micro-environment for reliable tau protein segmentation. In addition, by integrating visual interpretability, we are able to explain how the network focuses on a region of interest (ROI), giving additional insights to pathologists. Finally, the release of a new expert-annotated database and the code (\url{https://github.com/aramis-lab/miccai2022-stratifiad.git}) will be helpful for the scientific community to accelerate the development of new pipelines for human WSI processing in AD.

Neuroinflammation co‐localizes highly with tau in amnestic mild cognitive impairment

AbstractBackgroundNeuroinflammation, along with beta amyloid and tau brain deposition, is a potential diagnostic biomarker and therapeutic target in patients with Alzheimer’s disease (AD). The role of inflammation at various stages of the AD process needs to be clarified. TSPO PET is useful to image brain inflammation, but some tracers have low affinity for TSPO and “second generation” tracers, with higher affinity, cannot image subjects with a low‐binder TSPO rs6971 genotype. We overcame this problem by using 11C‐ER176, a high‐affinity tracer allowing for imaging of all participants and with a more favorable metabolite profile than other high affinity tracers (Fujita, 2017). Then, we correlated the localization of neuroinflammation tau and amyloid in a subset of the participants.MethodWe imaged 15 patients with amnestic MCI (mean age 63±5, 7 women) and 15 healthy controls (HC) (8/15 women, mean age 65 ±7) using 11C‐ER176 PET. TSPO affinity was similar (MCI/HC = 2/3 low, 8/7 mixed, 5/5 high). A full factorial analysis was performed on V T values between groups at the regional level (Hammer’s atlas). Ten MCI patients had also amyloid PET (18F‐florbetaben or 18F‐florbetapir) and tau PET (18F‐flortaucipir). Standard uptake value ratios (SUVRs) were calculated for both tracers using the cerebellum as reference. Regional correlations among the three tracers were determined for each patient and an average calculated. All images were corrected for partial volume effect.ResultNeuroinflammation in MCI was bilaterally increased in precuneus and lateral temporo‐ parietal cortex, and right amygdala. There was a correlation between the localization of amyloid and tau in the brain (r=0.61). However, the correlation between neuroinflammation and tau was even higher (r=0.73); neuroinflammation also co‐localized with amyloid, but not as strongly (r=0.59).Conclusion 11C‐ER176 PET allowed for the identification in MCI of neuroinflammation in regions known to be involved in the AD process. Importantly, all subjects with any TSPO genotype could be studied. As expected, the localization of amyloid and tau in the brain was correlated, but the co‐localization of neuroinflammation with tau was even higher than between amyloid and tau. This finding highlights the importance of neuroinflammation as a biomarker of neurodegeneration and as a therapeutic target.

Altered L‐carnitine and acylcarnitine profiles in APOE e4 carriers with Alzheimer’s disease reflect impaired fatty acid oxidation.

AbstractBackgroundAbnormal lipid metabolism is now considered one of the key biological features of Alzheimer’s disease (AD). The L‐carnitine system plays an important role in lipid metabolism, particularly fatty acid (FA) transport and metabolism in mitochondria. Blood and tissue acylcarnitine accumulation reflects incomplete fatty acid beta‐oxidation (FAO), corresponding with insulin resistance, oxidative stress and inflammation. We hypothesized that changes in blood and brain markers of the L‐carnitine system would indicate dysfunctional FAO in aging e4 carriers, thereby influencing AD pathogenesis.MethodPlasma and brain L‐carnitine, L‐carnitine metabolites and acylcarnitine were analyzed in controls and patients with early or moderate AD stratified by APOE genotypes. The L‐carnitine system was examined over a range of ages (10 to 50 weeks) in plasma and brains from transgenic mice expressing different human APOE isoforms and EFAD mice with human APOE and 5 x AD mutations.ResultAmong e4 carriers, plasma L‐carnitine decreased, but its metabolite, Trimethylamine N‐oxide, increased in patients with early or moderate AD. Among non‐e4 carriers these changes are detected only in moderate AD patients. Among e4 carriers, plasma long chain acylcarnitines (LCA) and very‐LCA (VLCA) were lowest in moderate AD patients. In e4 carriers, plasma acylcarnitines correlated with cerebrovascular, amyloid and tau pathologies. Whereas in e2 carriers, both brain and plasma acylcarnitines were correlated with amyloid, tau and cerebrovascular pathologies. In APOE4‐TR mice, medium chain acylcarnitines (MCA) and LCA decreased with age within the cerebrovasculature. Parenchymal acylcarnitines increased at an earlier age (25 weeks) among APOE4‐TR mice compared to mice with other APOE genotypes (50 weeks).ConclusionThese data suggest that among e4 carriers, the L‐carnitine system‐mediated FAO is dysregulated early in the disease process of AD. Age‐dependent decreases in MCA and LCA in the cerebrovasculature in APOE4‐TR compared to APOE3‐TR mice indicate FAO deficits at an earlier age in APOE4‐TR. Understanding the role of APOE4 in impaired FAO with age in relation to the L‐carnitine system is required for developing novel preventative/therapeutic strategies for AD.

Infectious origin of Alzheimer’s disease: Amyloid beta as a component of brain antimicrobial immunity

The amyloid cascade hypothesis, focusing on pathological proteins aggregation, has so far failed to uncover the root cause of Alzheimer's disease (AD), or to provide an effective therapy. This traditional paradigm essentially explains a mechanism involved in the development of sporadic AD rather than its cause. The failure of an overwhelming majority of clinical studies (99.6%) demonstrates that a breakthrough in therapy would be difficult if not impossible without understanding the etiology of AD. It becomes more and more apparent that the AD pathology might originate from brain infection. In this review, we discuss a potential role of bacteria, viruses, fungi, and eukaryotic parasites as triggers of AD pathology. We show evidence from the current literature that amyloid beta, traditionally viewed as pathological, actually acts as an antimicrobial peptide, protecting the brain against pathogens. However, in case of a prolonged or excessive activation of a senescent immune system, amyloid beta accumulation and aggregation becomes damaging and supports runaway neurodegenerative processes in AD. This is paralleled by the recent study by Alam and colleagues (2022) who showed that alpha-synuclein, the protein accumulating in synucleinopathies, also plays a critical physiological role in immune reactions and inflammation, showing an unforeseen link between the 2 unrelated classes of neurodegenerative disorders. The multiplication of the amyloid precursor protein gene, recently described by Lee and collegues (2018), and possible reactivation of human endogenous retroviruses by pathogens fits well into the same picture. We discuss these new findings from the viewpoint of the infection hypothesis of AD and offer suggestions for future research.

Intestinal Flora Affect Alzheimer's Disease by Regulating Endogenous Hormones.

Alzheimer's disease (AD) is a central nervous system disease that can lead to cognitive impairment and progressive memory loss. An increasing number of studies have shown that intestinal flora play a crucial role in regulating the brain-gut axis. Short-chain fatty acids are metabolites of intestinal flora that regulate hormone synthesis and play an essential role in microbial-intestinal-brain communication. An imbalance of intestinal flora can promote microglia to secrete proinflammatory factors, cause nerve inflammation, and then affect cognitive and learning ability. However, the mechanism is not clear. From this, we infer that endogenous hormones may be the medium for intestinal flora to affect the process of AD. This review of the relationships among AD, endogenous hormones, and intestinal flora expounds on the critical role of various hormones in the brain-gut axis. It discusses intervention measures aimed at intestinal flora to prevent or delay AD occurrence. Finally, the potential development prospects of fecal microbiota transplantation in treating AD are put forward, which provide potential ideas for future AD research.

Deletion of Small GTPase H-Ras Rescues Memory Deficits and Reduces Amyloid Plaque-Associated Dendritic Spine Loss in Transgenic Alzheimer's Mice.

Alzheimer's disease (AD) is a fatal neurodegenerative disorder, affecting millions of lives without a cure. While the molecular mechanism of AD remains obscure, emerging evidence suggests that small GTPases, a group of GTP-binding proteins that regulate a plethora of essential cellular events, modulate the pathogenic process of AD. Among those, the small GTPase H-Ras, extensively studied in cancer, regulates synaptic function, and both upstream and downstream signaling pathways of H-Ras have been implicated in AD. However, the role of H-Ras per se in AD pathogenesis had not been explored previously. In the present study, the impact of Hras deletion on cognitive function and amyloid pathology was investigated in transgenic APP/PS1 mice of AD. Behavioral assessments showed that the absence of Hras rescued spatial memory deficit in APP/PS1 mice at 9 months of age. The pathological evaluation demonstrated that Hras deletion reduced cortical amyloid deposition and astrogliosis. Furthermore, Hras deficiency protected against amyloid plaque-associated loss of dendritic spines in APP/PS1 mice. Intriguingly, canonical signaling pathways downstream of H-Ras were not affected by the absence of Hras in the brain. Unbiased transcriptomic analysis revealed that lack of H-Ras affected the expression of select genes in the brain of AD mice and identified a novel connection between H-Ras and Annexin A4, a calcium-dependent phospholipid-binding protein that has been shown to regulate membrane repair, neuroinflammation, and calcium homeostasis. Taken together, these data indicate that H-Ras modifies the pathogenic process of AD and may serve as a potential therapeutic target for AD.

Exercise as a Potential Therapeutic Strategy to Target the Clinical Link Between Depression and Alzheimer's Disease: A Narrative Review.

Alzheimer's disease (AD) and major depressive disorder (MDD) affect millions worldwide and both cause significant morbidity and mortality. While clinically distinctive, patients with MDD can present with memory dysfunction and patients with AD commonly report symptoms of depression. Additionally, brain pathology in MDD and AD both demonstrate decreased hippocampal volumes, and severe disease is associated with smaller hippocampal volumes in both disorders. Hippocampal neurogenesis occurs daily in healthy individuals, an impaired process in AD and MDD. MDD is thus suggested to be a risk factor for developing AD later in life; moreover, depression onset alongside AD indicates a worse prognosis. Treatment options that target hippocampal neurogenesis are being evaluated for both diseases, and aerobic exercise has shown promising results. We searched PubMed for relevant review articles published since 2000 encompassing the topics of hippocampal neurogenesis and exercise in relation to depression and AD, including novel clinical trials if they contributed information not in the chosen reviews. While much data indicates that exercise increases hippocampal neurogenesis in both MDD and AD, mood improvement in MDD, mild quality of life and cognitive improvement in AD, and reduced risk of those with MDD developing AD in response to various exercise regimens, this result was not universal. Some data indicated no difference between exercise groups and controls. Further randomized control trials into exercise as an intervention in treating MDD and preventing AD is required. However, exercise is a low-risk, affordable treatment option and is a feasible additive therapy in patients with AD and MDD.

Aberrant Energy Metabolism in Alzheimer's Disease.

To maintain energy supply to the brain, a direct energy source called adenosine triphosphate (ATP) is produced by oxidative phosphorylation and aerobic glycolysis of glucose in the mitochondria and cytoplasm. Brain glucose metabolism is reduced in many neurodegenerative diseases, including Alzheimer's disease (AD), where it appears presymptomatically in a progressive and region-specific manner. Following dysregulation of energy metabolism in AD, many cellular repair/regenerative processes are activated to conserve the energy required for cell viability. Glucose metabolism plays an important role in the pathology of AD and is closely associated with the tricarboxylic acid cycle, type 2 diabetes mellitus, and insulin resistance. The glucose intake in neurons is from endothelial cells, astrocytes, and microglia. Damage to neurocentric glucose also damages the energy transport systems in AD. Gut microbiota is necessary to modulate bidirectional communication between the gastrointestinal tract and brain. Gut microbiota may influence the process of AD by regulating the immune system and maintaining the integrity of the intestinal barrier. Furthermore, some therapeutic strategies have shown promising therapeutic effects in the treatment of AD at different stages, including the use of antidiabetic drugs, rescuing mitochondrial dysfunction, and epigenetic and dietary intervention. This review discusses the underlying mechanisms of alterations in energy metabolism in AD and provides potential therapeutic strategies in the treatment of AD.

Novel brain PET imaging agents: Strategies for imaging neuroinflammation in Alzheimer's disease and mild cognitive impairment.

Alzheimer’s disease (AD) is a devastating neurodegenerative disease with a concealed onset and continuous deterioration. Mild cognitive impairment (MCI) is the prodromal stage of AD. Molecule-based imaging with positron emission tomography (PET) is critical in tracking pathophysiological changes among AD and MCI patients. PET with novel targets is a promising approach for diagnostic imaging, particularly in AD patients. Our present review overviews the current status and applications of in vivo molecular imaging toward neuroinflammation. Although radiotracers can remarkably diagnose AD and MCI patients, a variety of limitations prevent the recommendation of a single technique. Recent studies examining neuroinflammation PET imaging suggest an alternative approach to evaluate disease progression. This review concludes that PET imaging towards neuroinflammation is considered a promising approach to deciphering the enigma of the pathophysiological process of AD and MCI.

Effects and mechanism of Aβ1−42 on EV-A71 replication

Backgroundβ-Amyloid (Aβ) protein is a pivotal pathogenetic factor in Alzheimer’s disease (AD). However, increasing evidence suggests that the brain has to continuously produce excessive Aβ to efficaciously prevent pathogenic micro-organism infections, which induces and accelerates the disease process of AD. Meanwhile, Aβ exhibits activity against herpes simplex virus type 1 (HSV-1) and influenza A virus (IAV) replication, but not against other neurotropic viruses. Enterovirus A71 (EV-A71) is the most important neurotropic enterovirus in the post-polio era. Given the limitation of existing research on the relationship between Aβ and other virus infections, this study aimed to investigate the potent activity of Aβ on EV-A71 infection and extended the potential function of Aβ in other unenveloped viruses may be linked to Alzheimer's disease or infectious neurological diseases.MethodsAβ peptides 1–42 are a major pathological factor of senile plaques in Alzheimer’s disease (AD). Thus, we utilized Aβ1–42 as a test subject to perform our study. The production of monomer Aβ1–42 and their high-molecular oligomer accumulations in neural cells were detected by immunofluorescence assay, ELISA, or Western blot assay. The inhibitory activity of Aβ1–42 peptides against EV-A71 in vitro was detected by Western blot analysis or qRT-PCR. The mechanism of Aβ1–42 against EV-A71 replication was analyzed by time-of-addition assay, attachment inhibition assay, pre-attachment inhibition analysis, viral-penetration inhibition assay, TEM analysis of virus agglutination, and pull-down assay.ResultsWe found that EV-A71 infection induced Aβ production and accumulation in SH-SY5Y cells. We also revealed for the first time that Aβ1–42 efficiently inhibited the RNA level of EV-A71 VP1, and the protein levels of VP1, VP2, and nonstructural protein 3AB in SH-SY5Y, Vero, and human rhabdomyosarcoma (RD) cells. Mechanistically, we demonstrated that Aβ1–42 primarily targeted the early stage of EV-A71 entry to inhibit virus replication by binding virus capsid protein VP1 or scavenger receptor class B member 2. Moreover, Aβ1–42 formed non-enveloped EV-A71 particle aggregates within a certain period and bound to the capsid protein VP1, which partially caused Aβ1–42 to prevent viruses from infecting cells.ConclusionsOur findings unveiled that Aβ1–42 effectively inhibited nonenveloped EV-A71 by targeting the early phase of an EV-A71 life cycle, thereby extending the potential function of Aβ in other non-envelope viruses linked to infectious neurological diseases.

Association between ambient air pollution exposure and plasma β-amyloid levels in the French Three-City study : preliminary results

Background: Existing research suggests an association between air pollution exposure and Alzheimer’s Disease (AD). However, underlying biological mechanisms are still unknown. We aimed to evaluate if air pollution exposure was associated with plasma β-amyloid (Aβ) levels. Methods: We selected 287 participants of the Three-City study who were cognitively unimpaired at 12-year follow-up. Aβ levels were measured on plasma samples stored at baseline and at 10 years (INNO-BIA plasma Aβ forms kits (Innogenetics)). Land-use regression models were used to estimate fine particulate matter (PM2.5), nitrogen dioxide (NO2) and black carbon (BC) exposure at participants’ residential address over the 5-year preceding the baseline visit. Linear regression was performed to assess the association of each pollutant with plasma Aβ levels at baseline and with their evolution over time. Results: Participants’ median age at baseline was 68.8 (IQR: 5.1), and 56.1% were women. Median levels (IQR) of plasma Aβ at baseline were 158.8 (37.5) pg/mL for Aβ1-40 and 41.4 (11.9) pg/mL for Aβ1-42. Median Aβ1-42/Aβ1-40 ratio was 0.255 (IQR: 0.065). We found that exposure to the three air pollutants was associated with decreased Aβ1-42/Aβ1-40 ratio at baseline. For instance, an IQR increase in PM2.5 (1.8 µg/m3) was associated with a 0.0119 decrease in the Aβ ratio (95% CI: -0.0209; -0.0029). There were no significant associations between air pollutants and Aβ evolution over time. Conclusion: In our cognitively unimpaired population, exposure to air pollution was associated with decreased plasma Aβ ratio at baseline. These results seem to corroborate previous ones on air pollution detrimental effect on cognition, as a decreased plasma Aβ ratio may predict AD. Further longitudinal studies using cutting edge methods to quantify plasmatic Aβ levels and brain Aβ deposits are still needed to better understand the influence of air pollution on the neuropathological process in AD. Keywords: Air pollution, Alzheimer’s Disease, Biomarkers

Iron dyshomeostasis and ferroptosis in Alzheimer's disease: Molecular mechanisms of cell death and novel therapeutic drugs and targets for AD.

Alzheimer’s disease (AD) is a degenerative disease of the central nervous system that is the most common type of senile dementia. Ferroptosis is a new type of iron-dependent programmed cell death identified in recent years that is different from other cell death forms. Ferroptosis is induced by excessive accumulation of lipid peroxides and reactive oxygen species (ROS) in cells. In recent years, it has been found that ferroptosis plays an important role in the pathological process of AD. Iron dyshomeostasis contribute to senile plaques (SP) deposition and neurofibrillary tangles (NFTs). Iron metabolism imbalance in brain and the dysfunction of endogenous antioxidant systems including system Xc- and glutathione peroxidase (GPX) are closely related to the etiopathogenesis of AD. Dysfunction of nuclear receptor coactivator 4 (NCOA4)-mediated ferritinophagy induced ferroptosis can accelerates the pathological process of AD. In addition, NRF2, through regulating the expression of a considerable number of genes related to ferroptosis, including genes related to iron and glutathione metabolism, plays an important role in the development of AD. Here, we review the potential interaction between AD and ferroptosis and the major pathways regulating ferroptosis in AD. We also review the active natural and synthetic compounds such as iron chelators, lipid peroxidation inhibitors and antioxidants available to treat AD by alleviating iron dyshomeostasis and preventing ferroptosis in mice and cell models to provide valuable information for the future treatment and prevention of AD.

Development of novel near-infrared GFP chromophore-based fluorescent probes for imaging of amyloid-β plaque and viscosity

Alzheimer's disease (AD) is closely associated with abnormal deposition of amyloid β (Aβ) peptides and formation of plaques. Green fluorescent protein (GFP) chromophores with a high-quality biomimetic fluorophore skeleton, have been extensively explored in biomedical diagnosis. However, its applications in intact animals were highly limited due to their short excitations and emissions owing to the absorption, scattering and auto-fluorescence by endogenous substances. In this work, through π-extension of the double bond bridge between the aromatic and imidazolidinone rings of the GFP chromophore, the emission of CX1 reached NIR window (over 702 nm) and what’s more interesting, the affinity of CX1 with Aβ aggregates was obviously improved. CX1 effectively avoided the limit in vivo imaging due to short excitation and emission and showed higher selectivity and signal-to-noise ratio towards Aβ plaques. In the hydrophobic cavity of Aβ aggregates or increased viscosity, the free rotation of CX1 was efficiently limited due to inhibition of twisted intramolecular charge transfer and thus the fluorescence emission exhibited a significant increase. Furthermore, CX1 can clearly image Aβ aggregates in the brain of transgenic mice and viscosity in living cells, which could serve as an effective tool for monitoring the pathological process of AD.

The trend of disruption in the functional brain network topology of Alzheimer’s disease

Alzheimer’s disease (AD) is a progressive disorder associated with cognitive dysfunction that alters the brain’s functional connectivity. Assessing these alterations has become a topic of increasing interest. However, a few studies have examined different stages of AD from a complex network perspective that cover different topological scales. This study used resting state fMRI data to analyze the trend of functional connectivity alterations from a cognitively normal (CN) state through early and late mild cognitive impairment (EMCI and LMCI) and to Alzheimer’s disease. The analyses had been done at the local (hubs and activated links and areas), meso (clustering, assortativity, and rich-club), and global (small-world, small-worldness, and efficiency) topological scales. The results showed that the trends of changes in the topological architecture of the functional brain network were not entirely proportional to the AD progression. There were network characteristics that have changed non-linearly regarding the disease progression, especially at the earliest stage of the disease, i.e., EMCI. Further, it has been indicated that the diseased groups engaged somatomotor, frontoparietal, and default mode modules compared to the CN group. The diseased groups also shifted the functional network towards more random architecture. In the end, the methods introduced in this paper enable us to gain an extensive understanding of the pathological changes of the AD process.

Retinal Ganglion Cell Complex in Alzheimer Disease: Comparing Ganglion Cell Complex and Central Macular Thickness in Alzheimer Disease and Healthy Subjects Using Spectral Domain-Optical Coherence Tomography.

Alzheimer disease (AD) is the most common form of dementia worldwide. The modalities to diagnose AD are generally expensive and limited. Both the central nervous system (CNS) and the retina are derived from the cranial neural crest; therefore, changes in retinal layers may reflect changes in the CNS tissue. Optical coherence tomography (OCT) machine can show delicate retinal layers and is widely used for retinal disorders. This study aims to find a new biomarker to help clinicians diagnose AD via retinal OCT examination. After considering the inclusion and exclusion criteria, 25 patients with mild and moderate AD and 25 healthy subjects were enrolled in the study. OCT was done for all eyes. The central macular thickness (CMT) and the ganglion cell complex (GCC) thickness were calculated. The groups were compared using the SPSS software, v. 22. Both GCC thickness and CMT were significantly decreased in patients with AD when compared to healthy age- and sex-matched individuals. Retinal changes, specifically CMT and GCC thickness, may reflect the AD process in the brain. OCT can be considered a non-invasive and inexpensive method to help diagnose AD.

Targeted Mitochondrial Epigenetics: A New Direction in Alzheimer's Disease Treatment.

Mitochondrial epigenetic alterations are closely related to Alzheimer’s disease (AD), which is described in this review. Reports of the alteration of mitochondrial DNA (mtDNA) methylation in AD demonstrate that the disruption of the dynamic balance of mtDNA methylation and demethylation leads to damage to the mitochondrial electron transport chain and the obstruction of mitochondrial biogenesis, which is the most studied mitochondrial epigenetic change. Mitochondrial noncoding RNA modifications and the post-translational modification of mitochondrial nucleoproteins have been observed in neurodegenerative diseases and related diseases that increase the risk of AD. Although there are still relatively few mitochondrial noncoding RNA modifications and mitochondrial nuclear protein post-translational modifications reported in AD, we have reason to believe that these mitochondrial epigenetic modifications also play an important role in the AD process. This review provides a new research direction for the AD mechanism, starting from mitochondrial epigenetics. Further, this review summarizes therapeutic approaches to targeted mitochondrial epigenetics, which is the first systematic summary of therapeutic approaches in the field, including folic acid supplementation, mitochondrial-targeting antioxidants, and targeted ubiquitin-specific proteases, providing a reference for therapeutic targets for AD.

Novel melatonin-trientine conjugate as potential therapeutic agents for Alzheimer’s disease

Researchers continue to explore drug targets to treat the characteristic pathologies of Alzheimer's disease (AD). Some drugs relieve the pathological processes of AD to some extent, but the failed clinical trials indicate that multifunctional agents seem more likely to achieve the therapy goals for this neurodegenerative disease. Herein, a novel compound named melatonin-trientine (TM) has been covalently synthesized with the natural antioxidant compounds melatonin and the metal ion chelator trientine. After toxicological and pharmacokinetic verification, we elucidated the effects of intraperitoneal administration of TM on AD-like pathology in 6-month-old mice that express both the β-amyloid (Aβ) precursor protein and presenilin-1 (APP/PS1). We found that TM significantly decreased Aβ deposition and neuronal degeneration in the brains of the APP/PS1 double transgenic mice. This result may be due to the upregulation of iron regulatory protein-2 (IRP2), insulin degrading enzyme (IDE), and low density lipoprotein receptor related protein 1 (LRP1), which leads to decreases in APP and Aβ levels. Additionally, TM may promote APP non-amyloidogenic processing by activating the melatonin receptor-2 (MT2)-dependent signaling pathways, but not MT1. In addition, TM plays an important role in blocking γ-secretase, tau hyperphosphorylation, neuroinflammation, oxidative stress, and metal ion dyshomeostasis. Our results suggest that TM may effectively maximize the therapeutic efficacy of targeting multiple mechanisms associated with AD pathology.

Elevated Levels of Naturally-Occurring Autoantibodies Against the Extracellular Domain of p75NTR Aggravate the Pathology of Alzheimer's Disease.

The extracellular domain (p75ECD) of p75 neurotrophin receptor (p75NTR) antagonizes Aβ neurotoxicity and promotes Aβ clearance in Alzheimer's disease (AD). The impaired shedding of p75ECD is a key pathological process in AD, but its regulatory mechanism is largely unknown. This study was designed to investigate the presence and alterations of naturally-occurring autoantibodies against p75ECD (p75ECD-NAbs) in AD patients and their effects on AD pathology. We found that the cerebrospinal fluid (CSF) level of p75ECD-NAbs was increased in AD, and negatively associated with the CSF levels of p75ECD. Transgenic AD mice actively immunized with p75ECD showed a lower level of p75ECD and more severe AD pathology in the brain, as well as worse cognitive functions than the control groups, which were immunized with Re-p75ECD (the reverse sequence of p75ECD) and phosphate-buffered saline, respectively. These findings demonstrate the impact of p75ECD-NAbs on p75NTR/p75ECD imbalance, providing a novel insight into the role of autoimmunity and p75NTR in AD.