The crosstalk between extracellular matrix proteins and Tau.

Alzheimer's disease is progressive neurodegenerative disease characterize by the presence of extracellular accumulation of amyloid-ß plaques and intracellular deposits of neurofibrillary tangles of Tau. Apart from axonal depositions pathological aggregated Tau protein is known to secrete into extracellular spaces and propagate through seeding mechanism. Microglia, the immune cells of the brain display modest ability to internalize the extracellular Tau and degrade it through endolysosomal pathway. However, the excessive burden of pathoproteins weakens the phagocytic ability of microglia. Extracellular supplementation of omega-3 fatty acids (n-3) may regulate the phagocytosis of microglia as they mediate the anti-inflammatory polarization of microglia through membrane lipid compositions changes. The internalization of extracellular Tau in the microglia is regulated by cortical membrane-associated actin remodeling driven by interplay of actin-binding proteins. On the other hand, Tau display capability bind and interact with various actin-binding protein owing to the presence of proline-rich domain in the structure and regulate their activation. In this study, we hypothesize that internalization of Tau in the presence of omega-3 fatty acids would propagate the Tau-mediated activation of actin-binding proteins as well as extracellular matrix and in turn modulate cortical actin remodeling for phagocytosis.

Calcium (Ca2+) hemostasis, mitochondria, autophagy, and mitophagy contribute to Alzheimer's disease as early moderators.

This review rigorously investigates the early cerebral changes associated with Alzheimer's disease, which manifest long before clinical symptoms arise. It presents evidence that the dysregulation of calcium (Ca2+) homeostasis, along with mitochondrial dysfunction and aberrant autophagic processes, may drive the disease's progression during its asymptomatic, preclinical stage. Understanding the intricate molecular interplay that unfolds during this critical period offers a window into identifying novel therapeutic targets, thereby advancing the treatment of neurodegenerative disorders. The review delves into both established and emerging insights into the molecular alterations precipitated by the disruption of Ca2+ balance, setting the stage for cognitive decline and neurodegeneration.

Dysregulated expression of miR-140 and miR-122 compromised microglial chemotaxis and led to reduced restriction of AD pathology.

BACKGROUND: Deposition of amyloid ß, which is produced by amyloidogenic cleavage of APP by ß- and γ-secretase, is one of the primary hallmarks of AD pathology. APP can also be processed by α- and γ-secretase sequentially, to generate sAPPα, which has been shown to be neuroprotective by promoting neurite outgrowth and neuronal survival, etc. METHODS: The global expression profiles of miRNA in blood plasma samples taken from 11 AD patients as well as from 14 age and sex matched cognitively normal volunteers were analyzed using miRNA-seq. Then, overexpressed miR-140 and miR-122 both in vivo and in vitro, and knock-down of the endogenous expression of miR-140 and miR-122 in vitro. Used a combination of techniques, including molecular biology, immunohistochemistry, to detect the impact of miRNAs on AD pathology. RESULTS: In this study, we identified that two miRNAs, miR-140-3p and miR-122-5p, both targeting ADAM10, the main α-secretase in CNS, were upregulated in the blood plasma of AD patients. Overexpression of these two miRNAs in mouse brains induced cognitive decline in wild type C57BL/6J mice as well as exacerbated dyscognition in APP/PS1 mice. Although significant changes in APP and total Aß were not detected, significantly downregulated ADAM10 and its non-amyloidogenic product, sAPPα, were observed in the mouse brains overexpressing miR-140/miR-122. Immunohistology analysis revealed increased neurite dystrophy that correlated with the reduced microglial chemotaxis in the hippocampi of these mice, independent of the other two ADAM10 substrates (neuronal CX3CL1 and microglial TREM2) that were involved in regulating the microglial immunoactivity. Further in vitro analysis demonstrated that both the reduced neuritic outgrowth of mouse embryonic neuronal cells overexpressing miR-140/miR-122 and the reduced Aß phagocytosis in microglia cells co-cultured with HT22 cells overexpressing miR-140/miR-122 could be rescued by overexpressing the specific inhibitory sequence of miR-140/miR-122 TuD as well as by addition of sAPPα, rendering these miRNAs as potential therapeutic targets. CONCLUSIONS: Our results suggested that neuroprotective sAPPα was a key player in the neuropathological progression induced by dysregulated expression of miR-140 and miR-122. Targeting these miRNAs might serve as a promising therapeutic strategy in AD treatment.

Structure focused neurodegeneration convolutional neural network for modelling and classification of Alzheimer's disease.

Alzheimer's disease (AD), the predominant form of dementia, is a growing global challenge, emphasizing the urgent need for accurate and early diagnosis. Current clinical diagnoses rely on radiologist expert interpretation, which is prone to human error. Deep learning has thus far shown promise for early AD diagnosis. However, existing methods often overlook focal structural atrophy critical for enhanced understanding of the cerebral cortex neurodegeneration. This paper proposes a deep learning framework that includes a novel structure-focused neurodegeneration CNN architecture named SNeurodCNN and an image brightness enhancement preprocessor using gamma correction. The SNeurodCNN architecture takes as input the focal structural atrophy features resulting from segmentation of brain structures captured through magnetic resonance imaging (MRI). As a result, the architecture considers only necessary CNN components, which comprises of two downsampling convolutional blocks and two fully connected layers, for achieving the desired classification task, and utilises regularisation techniques to regularise learnable parameters. Leveraging mid-sagittal and para-sagittal brain image viewpoints from the Alzheimer's disease neuroimaging initiative (ADNI) dataset, our framework demonstrated exceptional performance. The para-sagittal viewpoint achieved 97.8% accuracy, 97.0% specificity, and 98.5% sensitivity, while the mid-sagittal viewpoint offered deeper insights with 98.1% accuracy, 97.2% specificity, and 99.0% sensitivity. Model analysis revealed the ability of SNeurodCNN to capture the structural dynamics of mild cognitive impairment (MCI) and AD in the frontal lobe, occipital lobe, cerebellum, temporal, and parietal lobe, suggesting its potential as a brain structural change digi-biomarker for early AD diagnosis. This work can be reproduced using code we made available on GitHub.

Choroid plexus volume as a novel candidate neuroimaging marker of the Alzheimer's continuum.

BACKGROUND: Enlarged choroid plexus (ChP) volume has been reported in patients with Alzheimer's disease (AD) and inversely correlated with cognitive performance. However, its clinical diagnostic and predictive value, and mechanisms by which ChP impacts the AD continuum remain unclear. METHODS: This prospective cohort study enrolled 607 participants [healthy control (HC): 110, mild cognitive impairment (MCI): 269, AD dementia: 228] from the Chinese Imaging, Biomarkers, and Lifestyle study between January 1, 2021, and December 31, 2022. Of the 497 patients on the AD continuum, 138 underwent lumbar puncture for cerebrospinal fluid (CSF) hallmark testing. The relationships between ChP volume and CSF pathological hallmarks (Aß42, Aß40, Aß42/40, tTau, and pTau181), neuropsychological tests [Mini-Mental State Examination (MMSE), Montreal Cognitive Assessment (MoCA), Neuropsychiatric Inventory (NPI), and Activities of Daily Living (ADL) scores], and multimodal neuroimaging measures [gray matter volume, cortical thickness, and corrected cerebral blood flow (cCBF)] were analyzed using partial Spearman's correlation. The mediating effects of four neuroimaging measures [ChP volume, hippocampal volume, lateral ventricular volume (LVV), and entorhinal cortical thickness (ECT)] on the relationship between CSF hallmarks and neuropsychological tests were examined. The ability of the four neuroimaging measures to identify cerebral Aß42 changes or differentiate among patients with AD dementia, MCI and HCs was determined using receiver operating characteristic analysis, and their associations with neuropsychological test scores at baseline were evaluated by linear regression. Longitudinal associations between the rate of change in the four neuroimaging measures and neuropsychological tests scores were evaluated on the AD continuum using generalized linear mixed-effects models. RESULTS: The participants' mean age was 65.99 ± 8.79 years. Patients with AD dementia exhibited the largest baseline ChP volume than the other groups (P < 0.05). ChP volume enlargement correlated with decreased Aß42 and Aß40 levels; lower MMSE and MoCA and higher NPI and ADL scores; and lower volume, cortical thickness, and cCBF in other cognition-related regions (all P < 0.05). ChP volume mediated the association of Aß42 and Aß40 levels with MMSE scores (19.08% and 36.57%), and Aß42 levels mediated the association of ChP volume and MMSE or MoCA scores (39.49% and 34.36%). ChP volume alone better identified cerebral Aß42 changes than LVV alone (AUC = 0.81 vs. 0.67, P = 0.04) and EC thickness alone (AUC = 0.81 vs.0.63, P = 0.01) and better differentiated patients with MCI from HCs than hippocampal volume alone (AUC = 0.85 vs. 0.81, P = 0.01), and LVV alone (AUC = 0.85 vs.0.82, P = 0.03). Combined ChP and hippocampal volumes significantly increased the ability to differentiate cerebral Aß42 changes and patients among AD dementia, MCI, and HCs groups compared with hippocampal volume alone (all P < 0.05). After correcting for age, sex, years of education, APOE ε4 status, eTIV, and hippocampal volume, ChP volume was associated with MMSE, MoCA, NPI, and ADL score at baseline, and rapid ChP volume enlargement was associated with faster deterioration in NPI scores with an average follow-up of 10.03 ± 4.45 months (all P < 0.05). CONCLUSIONS: ChP volume may be a novel neuroimaging marker associated with neurodegenerative changes and clinical AD manifestations. It could better detect the early stages of the AD and predict prognosis, and significantly enhance the differential diagnostic ability of hippocampus on the AD continuum.

Identifying longitudinal cognitive resilience from cross-sectional amyloid, tau, and neurodegeneration.

BACKGROUND: Leveraging Alzheimer's disease (AD) imaging biomarkers and longitudinal cognitive data may allow us to establish evidence of cognitive resilience (CR) to AD pathology in-vivo. Here, we applied latent class mixture modeling, adjusting for sex, baseline age, and neuroimaging biomarkers of amyloid, tau and neurodegeneration, to a sample of cognitively unimpaired older adults to identify longitudinal trajectories of CR. METHODS: We identified 200 Harvard Aging Brain Study (HABS) participants (mean age = 71.89 years, SD = 9.41 years, 59% women) who were cognitively unimpaired at baseline with 2 or more timepoints of cognitive assessment following a single amyloid-PET, tau-PET and structural MRI. We examined latent class mixture models with longitudinal cognition as the dependent variable and time from baseline, baseline age, sex, neocortical Aß, entorhinal tau, and adjusted hippocampal volume as independent variables. We then examined group differences in CR-related factors across the identified subgroups from a favored model. Finally, we applied our favored model to a dataset from the Alzheimer's Disease Neuroimaging Initiative (ADNI; n = 160, mean age = 73.9 years, SD = 7.6 years, 60% women). RESULTS: The favored model identified 3 latent subgroups, which we labelled as Normal (71% of HABS sample), Resilient (22.5%) and Declining (6.5%) subgroups. The Resilient subgroup exhibited higher baseline cognitive performance and a stable cognitive slope. They were differentiated from other groups by higher levels of verbal intelligence and past cognitive activity. In ADNI, this model identified a larger Normal subgroup (88.1%), a smaller Resilient subgroup (6.3%) and a Declining group (5.6%) with a lower cognitive baseline. CONCLUSION: These findings demonstrate the value of data-driven approaches to identify longitudinal CR groups in preclinical AD. With such an approach, we identified a CR subgroup who reflected expected characteristics based on previous literature, higher levels of verbal intelligence and past cognitive activity.

Metallothionein III Decreases the Proliferation of Astrocytes and Enhances Pathological Improvements in a Mouse Model of Alzheimer's Disease.

BACKGROUND: Alzheimer's disease (AD) affects the brain and causes difficulties with cognition and emotions. At present, there are no viable therapies to halt or slow down the advancement of AD. Metallothionein III (MT-III) exhibits antioxidant and anti-inflammatory characteristics, indicating possible therapeutic benefits. This study aimed to explore the influence of MT-III on AD pathological alterations and cognitive abilities. METHODS: In this research, we employed the universally accepted AD mouse models (3xTg-AD) as test subjects and administrated vehicle or MT-III. The mice were subjected to the Morris water maze test to assess their spatial learning and memory capabilities. Moreover, to evaluate the consequent effects on neuronal groups in the hippocampus, the Nissl staining and neuronal nuclear antigen (NeuN) immunohistochemistry were used to identify the cellular morphology changes and density. Immunohistochemistry was also used to detect ß-amyloid (Aß) and glial fibrillary acidic protein (GFAP) to measure Aß accumulation and astrocyte growth. Western blot was also used to measure Tau pathology-related PHD finger protein 1 (PHF-1), phosphorylated Tau (AT-8), and total Tau protein. RESULTS: The administration of MT-III notably enhanced spatial learning and memory function in 3xTg-AD mice, as evidenced by the Morris water maze test (p < 0.01). According to immunohistochemistry and the obtained findings, it was observed that brain tissues of mice treated with MT-III showed a notable increase of Nissl bodies and NeuN intensity (p < 0.01) while a remarkable decrease in Aß accumulation and GFAP (p < 0.01). Additionally, MT-III largely decreased levels of Tau phosphorylation-related PHF-1 and AT-8 (p < 0.01) and slightly reduced the level of Tau 5 (p < 0.05). CONCLUSION: In summary, our research indicates that MT-III has the capacity to ameliorate pathological alterations in AD mouse models and safeguard their cognitive and emotional abilities. By decreasing ß-amyloid accumulation and reducing the intensity of Tau pathology, MT-III protected hippocampal subfield neurons against pathological harm. Furthermore, MT-III reduced inflammation by inhibiting abnormal proliferation of astrocytes. Of utmost importance, MT-III greatly enhanced the cognitive abilities related to spatial learning and memory in mice, suggesting its promising therapeutic properties for AD.

Behaviour Hallmarks in Alzheimer's Disease 5xFAD Mouse Model.

The 5xFAD transgenic mouse model widely used in Alzheimer's disease (AD) research recapitulates many AD-related phenotypes with a relatively early onset and aggressive age-dependent progression. Besides developing amyloid peptide deposits alongside neuroinflammation by the age of 2 months, as well as exhibiting neuronal decline by the age of 4 months that intensifies by the age of 9 months, these mice manifest a broad spectrum of behavioural impairments. In this review, we present the extensive repertoire of behavioural dysfunctions in 5xFAD mice, organised into four categories: motor skills, sensory function, learning and memory abilities, and neuropsychiatric-like symptoms. The motor problems, associated with agility and reflex movements, as well as balance and coordination, and skeletal muscle function, typically arise by the time mice reach 9 months of age. The sensory function (such as taste, smell, hearing, and vision) starts to deteriorate when amyloid peptide buildups and neuroinflammation spread into related anatomical structures. The cognitive functions, encompassing learning and memory abilities, such as visual recognition, associative, spatial working, reference learning, and memory show signs of decline from 4 to 6 months of age. Concerning neuropsychiatric-like symptoms, comprising apathy, anxiety and depression, and the willingness for exploratory behaviour, it is believed that motivational changes emerge by approximately 6 months of age. Unfortunately, numerous studies from different laboratories are often contradictory on the conclusions drawn and the identification of onset age, making preclinical studies in rodent models not easily translatable to humans. This variability is likely due to a range of factors associated with animals themselves, housing and husbandry conditions, and experimental settings. In the forthcoming studies, greater clarity in experimental details when conducting behavioural testing in 5xFAD transgenic mice could minimise the inconsistencies and could ensure the reliability and the reproducibility of the results.

Xenografted human iPSC-derived neurons with the familial Alzheimer's disease APPV717I mutation reveal dysregulated transcriptome signatures linked to synaptic function and implicate LINGO2 as a disease signaling mediator.

Alzheimer's disease (AD) is the most common cause of dementia, and disease mechanisms are still not fully understood. Here, we explored pathological changes in human induced pluripotent stem cell (iPSC)-derived neurons carrying the familial AD APPV717I mutation after cell injection into the mouse forebrain. APPV717I mutant iPSCs and isogenic controls were differentiated into neurons revealing enhanced Aß42 production, elevated phospho-tau, and impaired neurite outgrowth in APPV717I neurons. Two months after transplantation, APPV717I and control neural cells showed robust engraftment but at 12 months post-injection, APPV717I grafts were smaller and demonstrated impaired neurite outgrowth compared to controls, while plaque and tangle pathology were not seen. Single-nucleus RNA-sequencing of micro-dissected grafts, performed 2 months after cell injection, identified significantly altered transcriptome signatures in APPV717I iPSC-derived neurons pointing towards dysregulated synaptic function and axon guidance. Interestingly, APPV717I neurons showed an increased expression of genes, many of which are also upregulated in postmortem neurons of AD patients including the transmembrane protein LINGO2. Downregulation of LINGO2 in cultured APPV717I neurons rescued neurite outgrowth deficits and reversed key AD-associated transcriptional changes related but not limited to synaptic function, apoptosis and cellular senescence. These results provide important insights into transcriptional dysregulation in xenografted APPV717I neurons linked to synaptic function, and they indicate that LINGO2 may represent a potential therapeutic target in AD.

Cannabinerol Prevents Endoplasmic Reticulum and Mitochondria Dysfunctions in an In Vitro Model of Alzheimer's Disease: A Network-Based Transcriptomic Analysis.

Neurodegenerative disorders are affecting millions of people worldwide, impacting the healthcare system of our society. Among them, Alzheimer's disease (AD) is the most common form of dementia, characterized by severe cognitive impairments. Neuropathological hallmarks of AD are ß-amyloid (Aß) plaques and neurofibrillary tangles, as well as endoplasmic reticulum and mitochondria dysfunctions, which finally lead to apoptosis and neuronal loss. Since, to date, there is no definitive cure, new therapeutic and prevention strategies are of crucial importance. In this scenario, cannabinoids are deeply investigated as promising neuroprotective compounds for AD. In this study, we evaluated the potential neuroprotective role of cannabinerol (CBNR) in an in vitro cellular model of AD via next-generation sequencing. We observed that CBNR pretreatment counteracts the Aß-induced loss of cell viability of differentiated SH-SY5Y cells. Moreover, a network-based transcriptomic analysis revealed that CBNR restores normal mitochondrial and endoplasmic reticulum functions in the AD model. Specifically, the most important genes regulated by CBNR are related mainly to oxidative phosphorylation (COX6B1, OXA1L, MT-CO2, MT-CO3), protein folding (HSPA5) and degradation (CUL3, FBXW7, UBE2D1), and glucose (G6PC3) and lipid (HSD17B7, ERG28, SCD) metabolism. Therefore, these results suggest that CBNR could be a new neuroprotective agent helpful in the prevention of AD dysfunctions.

Sleep Disruption Precedes Forebrain Synaptic Tau Burden and Contributes to Cognitive Decline in a Sex-Dependent Manner in the P301S Tau Transgenic Mouse Model.

Sleep disruption and impaired synaptic processes are common features in neurodegenerative diseases, including Alzheimer's disease (AD). Hyperphosphorylated Tau is known to accumulate at neuronal synapses in AD, contributing to synapse dysfunction. However, it remains unclear how sleep disruption and synapse pathology interact to contribute to cognitive decline. Here, we examined sex-specific onset and consequences of sleep loss in AD/tauopathy model PS19 mice. Using a piezoelectric home-cage monitoring system, we showed PS19 mice exhibited early-onset and progressive hyperarousal, a selective dark-phase sleep disruption, apparent at 3 months in females and 6 months in males. Using the Morris water maze test, we report that chronic sleep disruption (CSD) accelerated the onset of decline of hippocampal spatial memory in PS19 males only. Hyperarousal occurs well in advance of robust forebrain synaptic Tau burden that becomes apparent at 6-9 months. To determine whether a causal link exists between sleep disruption and synaptic Tau hyperphosphorylation, we examined the correlation between sleep behavior and synaptic Tau, or exposed mice to acute or chronic sleep disruption at 6 months. While we confirm that sleep disruption is a driver of Tau hyperphosphorylation in neurons of the locus ceruleus, we were unable to show any causal link between sleep loss and Tau burden in forebrain synapses. Despite the finding that hyperarousal appears earlier in females, female cognition was resilient to the effects of sleep disruption. We conclude sleep disruption interacts with the synaptic Tau burden to accelerate the onset of cognitive decline with greater vulnerability in males.

Comprehensive assessment of TDP-43 neuropathology data in the National Alzheimer's Coordinating Center database.

TDP-43 proteinopathy is a salient neuropathologic feature in a subset of frontotemporal lobar degeneration (FTLD-TDP), in amyotrophic lateral sclerosis (ALS-TDP), and in limbic-predominant age-related TDP-43 encephalopathy neuropathologic change (LATE-NC), and is associated with hippocampal sclerosis of aging (HS-A). We examined TDP-43-related pathology data in the National Alzheimer's Coordinating Center (NACC) in two parts: (I) availability of assessments, and (II) associations with clinical diagnoses and other neuropathologies in those with all TDP-43 measures available. Part I: Of 4326 participants with neuropathology data collected using forms that included TDP-43 assessments, data availability was highest for HS-A (97%) and ALS (94%), followed by FTLD-TDP (83%). Regional TDP-43 pathologic assessment was available for 77% of participants, with hippocampus the most common region. Availability for the TDP-43-related measures increased over time, and was higher in centers with high proportions of participants with clinical FTLD. Part II: In 2142 participants with all TDP-43-related assessments available, 27% of participants had LATE-NC, whereas ALS-TDP or FTLD-TDP (ALS/FTLD-TDP) was present in 9% of participants, and 2% of participants had TDP-43 related to other pathologies ("Other TDP-43"). HS-A was present in 14% of participants, of whom 55% had LATE-NC, 20% ASL/FTLD-TDP, 3% Other TDP-43, and 23% no TDP-43. LATE-NC, ALS/FTLD-TDP, and Other TDP-43, were each associated with higher odds of dementia, HS-A, and hippocampal atrophy, compared to those without TDP-43 pathology. LATE-NC was associated with higher odds for Alzheimer's disease (AD) clinical diagnosis, AD neuropathologic change (ADNC), Lewy bodies, arteriolosclerosis, and cortical atrophy. ALS/FTLD-TDP was associated with higher odds of clinical diagnoses of primary progressive aphasia and behavioral-variant frontotemporal dementia, and cortical/frontotemporal lobar atrophy. When using NACC data for TDP-43-related analyses, researchers should carefully consider the incomplete availability of the different regional TDP-43 assessments, the high frequency of participants with ALS/FTLD-TDP, and the presence of other forms of TDP-43 pathology.

PTPRS is a novel marker for early Tau pathology and synaptic integrity in Alzheimer's disease.

We examined the role of protein tyrosine phosphatase receptor sigma (PTPRS) in the context of Alzheimer's disease and synaptic integrity. Publicly available datasets (BRAINEAC, ROSMAP, ADC1) and a cohort of asymptomatic but "at risk" individuals (PREVENT-AD) were used to explore the relationship between PTPRS and various Alzheimer's disease biomarkers. We identified that PTPRS rs10415488 variant C shows features of neuroprotection against early Tau pathology and synaptic degeneration in Alzheimer's disease. This single nucleotide polymorphism correlated with higher PTPRS transcript abundance and lower p(181)Tau and GAP-43 levels in the CSF. In the brain, PTPRS protein abundance was significantly correlated with the quantity of two markers of synaptic integrity: SNAP25 and SYT-1. We also found the presence of sexual dimorphism for PTPRS, with higher CSF concentrations in males than females. Male carriers for variant C were found to have a 10-month delay in the onset of AD. We thus conclude that PTPRS acts as a neuroprotective receptor in Alzheimer's disease. Its protective effect is most important in males, in whom it postpones the age of onset of the disease.

Crystal Violet Selectively Detects Aß Oligomers but Not Fibrils In Vitro and in Alzheimer's Disease Brain Tissue.

Deposition of extracellular Amyloid Beta (Aß) and intracellular tau fibrils in post-mortem brains remains the only way to conclusively confirm cases of Alzheimer's Disease (AD). Substantial evidence, though, implicates small globular oligomers instead of fibrils as relevant biomarkers of, and critical contributors to, the clinical symptoms of AD. Efforts to verify and utilize amyloid oligomers as AD biomarkers in vivo have been limited by the near-exclusive dependence on conformation-selective antibodies for oligomer detection. While antibodies have yielded critical evidence for the role of both Aß and tau oligomers in AD, they are not suitable for imaging amyloid oligomers in vivo. Therefore, it would be desirable to identify a set of oligomer-selective small molecules for subsequent development into Positron Emission Tomography (PET) probes. Using a kinetics-based screening assay, we confirm that the triarylmethane dye Crystal Violet (CV) is oligomer-selective for Aß42 oligomers (AßOs) grown under near-physiological solution conditions in vitro. In postmortem brains of an AD mouse model and human AD patients, we demonstrate that A11 antibody-positive oligomers but not Thioflavin S (ThioS)-positive fibrils colocalize with CV staining, confirming in vitro results. Therefore, our kinetic screen represents a robust approach for identifying new classes of small molecules as candidates for oligomer-selective dyes (OSDs). Such OSDs, in turn, provide promising starting points for the development of PET probes for pre-mortem imaging of oligomer deposits in humans.

Multifactor Analyses of Frontal Cortex Lipids in the APP/PS1 Model of Familial Alzheimer's Disease Reveal Anomalies in Responses to Dietary n-3 PUFA and Estrogenic Treatments.

Brain lipid homeostasis is an absolute requirement for proper functionality of nerve cells and neurological performance. Current evidence demonstrates that lipid alterations are linked to neurodegenerative diseases, especially Alzheimer's disease (AD). The complexity of the brain lipidome and its metabolic regulation has hampered the identification of critical processes associated with the onset and progression of AD. While most experimental studies have focused on the effects of known factors on the development of pathological hallmarks in AD, e.g., amyloid deposition, tau protein and neurofibrillary tangles, neuroinflammation, etc., studies addressing the causative effects of lipid alterations remain largely unexplored. In the present study, we have used a multifactor approach combining diets containing different amounts of polyunsaturated fatty acids (PUFAs), estrogen availabilities, and genetic backgrounds, i.e., wild type (WT) and APP/PS1 (FAD), to analyze the lipid phenotype of the frontal cortex in middle-aged female mice. First, we observed that severe n-3 PUFA deficiency impacts the brain n-3 long-chain PUFA (LCPUFA) composition, yet it was notably mitigated by hepatic de novo synthesis. n-6 LCPUFAs, ether-linked fatty acids, and saturates were also changed by the dietary condition, but the extent of changes was dependent on the genetic background and hormonal condition. Likewise, brain cortex phospholipids were mostly modified by the genotype (FAD>WT) with nuanced effects from dietary treatment. Cholesterol (but not sterol esters) was modified by the genotype (WT>FAD) and dietary condition (higher in DHA-free conditions, especially in WT mice). However, the effects of estrogen treatment were mostly observed in relation to phospholipid remodeling in a genotype-dependent manner. Analyses of lipid-derived variables indicate that nerve cell membrane biophysics were significantly affected by the three factors, with lower membrane microviscosity (higher fluidity) values obtained for FAD animals. In conclusion, our multifactor analyses revealed that the genotype, diet, and estrogen status modulate the lipid phenotype of the frontal cortex, both as independent factors and through their interactions. Altogether, the outcomes point to potential strategies based on dietary and hormonal interventions aimed at stabilizing the brain cortex lipid composition in Alzheimer's disease neuropathology.

Mitochondrial One-Carbon Metabolism and Alzheimer's Disease.

Mitochondrial one-carbon metabolism provides carbon units to several pathways, including nucleic acid synthesis, mitochondrial metabolism, amino acid metabolism, and methylation reactions. Late-onset Alzheimer's disease is the most common age-related neurodegenerative disease, characterised by impaired energy metabolism, and is potentially linked to mitochondrial bioenergetics. Here, we discuss the intersection between the molecular pathways linked to both mitochondrial one-carbon metabolism and Alzheimer's disease. We propose that enhancing one-carbon metabolism could promote the metabolic processes that help brain cells cope with Alzheimer's disease-related injuries. We also highlight potential therapeutic avenues to leverage one-carbon metabolism to delay Alzheimer's disease pathology.

Deciphering Early and Progressive Molecular Signatures in Alzheimer's Disease through Integrated Longitudinal Proteomic and Pathway Analysis in a Rodent Model.

Alzheimer's disease (AD), the leading cause of dementia worldwide, remains a challenge due to its complex origin and degenerative character. The need for accurate biomarkers and treatment targets hinders early identification and intervention. To fill this gap, we used a novel longitudinal proteome methodology to examine the temporal development of molecular alterations in the cortex of an intracerebroventricular streptozotocin (ICV-STZ)-induced AD mouse model for disease initiation and progression at one, three-, and six-weeks post-treatment. Week 1 revealed metabolic protein downregulation, such as Aldoa and Pgk1. Week 3 showed increased Synapsin-1, and week 6 showed cytoskeletal protein alterations like Vimentin. The biological pathways, upstream regulators, and functional effects of proteome alterations were dissected using advanced bioinformatics methods, including Ingenuity Pathway Analysis (IPA) and machine learning algorithms. We identified Mitochondrial Dysfunction, Synaptic Vesicle Pathway, and Neuroinflammation Signaling as disease-causing pathways. Huntington's Disease Signaling and Synaptogenesis Signaling were stimulated while Glutamate Receptor and Calcium Signaling were repressed. IPA also found molecular connections between PPARGC1B and AGT, which are involved in myelination and possible neoplastic processes, and MTOR and AR, which imply mechanistic involvements beyond neurodegeneration. These results help us comprehend AD's molecular foundation and demonstrate the promise of focused proteomic techniques to uncover new biomarkers and therapeutic targets for AD, enabling personalized medicine.

Enhancing Rab7 Activity by Inhibiting TBC1D5 Expression Improves Mitophagy in Alzheimer's Disease Models.

Background: Mitochondrial dysfunction exists in Alzheimer's disease (AD) brain, and damaged mitochondria need to be removed by mitophagy. Small GTPase Rab7 regulates the fusion of mitochondria and lysosome, while TBC1D5 inhibits Rab7 activation. However, it is not clear whether the regulation of Rab7 activity by TBC1D5 can improve mitophagy and inhibit AD progression. Objective: To investigate the role of TBC1D5 in mitophagy and its regulatory mechanism for Rab7, and whether activation of mitophagy can inhibit the progression of AD. Methods: Mitophagy was determined by western blot and immunofluorescence. The morphology and quantity of mitochondria were tracked by TEM. pCMV-Mito-AT1.03 was employed to detect the cellular ATP. Amyloid-ß secreted by AD cells was detected by ELISA. Co-immunoprecipitation was used to investigate the binding partner of the target protein. Golgi-cox staining was applied to observe neuronal morphology of mice. The Morris water maze test and Y-maze were performed to assess spatial learning and memory, and the open field test was measured to evaluate motor function and anxiety-like phenotype of experimental animals. Results: Mitochondrial morphology was impaired in AD models, and TBC1D5 was highly expressed. Knocking down TBC1D5 increased the expression of active Rab7, promoted the fusion of lysosome and autophagosome, thus improving mitophagy, and improved the morphology of hippocampal neurons and the impaired behavior in AD mice. Conclusions: Knocking down TBC1D5 increased Rab7 activity and promoted the fusion of autophagosome and lysosome. Our study provided insights into the mechanisms that bring new possibilities for AD therapy targeting mitophagy.

Plasma Insulin Predicts Early Amyloid-ß Pathology Changes in Alzheimer's Disease.

Background: Evidence suggests that type 2 diabetes (T2D) is an independent risk factor for Alzheimer's disease (AD), sharing similar pathophysiological traits like impaired insulin signaling. Objective: To test the association between plasma insulin and cerebrospinal fluid (CSF) AD pathology. Methods: A total of 304 participants were included in the Alzheimer's Disease Neuroimaging Initiative, assessing plasma insulin and CSF AD pathology. We explored the cross-sectional and longitudinal associations between plasma insulin and AD pathology and compared their associations across different AD clinical and pathological stages. Results: In the non-demented group, amyloid-ß (Aß)+ participants (e.g., as reflected by CSF Aß42) exhibited significantly lower plasma insulin levels compared to non-demented Aß-participants (p < 0.001). This reduction in plasma insulin was more evident in the A+T+ group (as shown by CSF Aß42 and pTau181 levels) when compared to the A-T- group within the non-dementia group (p = 0.002). Additionally, higher plasma insulin levels were consistently associated with more normal CSF Aß42 levels (p < 0.001) across all participants. This association was particularly significant in the Aß-group (p = 0.002) and among non-demented individuals (p < 0.001). Notably, baseline plasma insulin was significantly correlated with longitudinal changes in CSF Aß42 (p = 0.006), whereas baseline CSF Aß42 did not show a similar correlation with changes in plasma insulin over time. Conclusions: These findings suggest an association between plasma insulin and early Aß pathology in the early stages of AD, indicating that plasma insulin may be a potential predictor of changes in early Aß pathology.