Amyloid Pathology Research Articles

Mapping the evolving landscape of lecanemab research in Alzheimer's Disease: A bibliometric analysis.

A decade progress in the phenotyping of AppNL-G-F knock-in mouse model of Alzheimer's disease.

Comparison of the ApoE allelic variants in the formation of intracerebral Aβ deposits.

The importance of astrocytes for Alzheimer’s disease (AD) pathology is increasingly appreciated, yet the mechanisms whereby this cell type impacts neurodegenerative processes remain elusive. Here we show that, in a genetic mouse model with diminished astrocyte stress response, even low levels of amyloid-β trigger astrocyte reactivity, resulting in brain inflammation and massive amyloid and tau pathologies. This dysfunctional response of astrocytes to amyloid-β acts through activation of δ secretase, a stress-induced protease implicated in both amyloid and tau-related proteolytic processing. Our findings identify a failed astrocyte stress response to amyloid-β as an early inducer of amyloid and tau co-morbidity, a noxious process in AD acting through a non-canonical secretase pathway.

We studied the effect of a protein kinase A (PKA) inhibitor and the content of different types of progenitor cells in the subventricular zone of the brain of 16-month-old male C57BL/6 mice (characterized by pathological endogenous amyloid formation in the brain) and on the mental status of these mice. The pharmacological agent ameliorated disorders of orientation and exploratory behavior and conditioned response performance in experimental animals. At the same time, an increase in the content of resident neural stem cells and committed neuronal precursors in the nervous tissue was found.

BackgroundAlzheimer's disease (AD) is the leading cause of dementia in the elderly, characterized by cognitive decline, memory impairment, and neuronal and vascular dysfunction. Men and women respond differently to AD progression, with women at higher risk due to hormonal, metabolic, and immune differences that increase brain vulnerability. Physical exercise benefits brain health by improving cognition, modulating inflammation, and promoting vascular and neurotrophic activity. However, the long-term effects of resistance exercise (RE) on brain health, particularly regarding sex differences, remain unclear.ObjectiveThis study investigated the effects of a long-term RE protocol on the APP/PS1 transgenic mouse model, evaluating behavior, neurotrophic factor levels, and amyloid pathology in males and females.MethodsMale and female APP/PS1 and wild-type (WT) mice underwent a 4-month RE protocol using a ladder-climbing paradigm. Behavioral tests included open field, object recognition, and T-maze tests. Hippocampal tissue was analyzed via ELISA (VEGF, IGF-1, BDNF, Aβ) and immunohistochemistry (amyloid plaques).ResultsRE had sex-dependent effects. In female APP/PS1 mice, RE reduced hyperlocomotion, rescued short-term memory, increased VEGF levels, and reduced brain Aβ and plaque burden. In male APP/PS1 mice, RE rescued learning and long-term memory, increased IGF-1 and BDNF levels, and reduced hyperlocomotion, although no significant reduction in Aβ or plaque burden was observed.ConclusionsThese findings highlight sex-specific effects of RE in AD and suggest potential personalized exercise-based interventions for delaying disease progression.

BackgroundMicroRNAs (miRNAs) have emerged as key regulators in Alzheimer's disease (AD), yet their function as biomarkers remains uncertain due to inconsistent findings in blood and cerebrospinal fluid (CSF).ObjectiveWe aimed to identify miRNAs that track disease progression, providing valuable insights into AD pathophysiology.MethodsThis study focused on analyzing alterations in miRNA expression levels in CSF and plasma samples, and their association with cognitive decline and hippocampal volume changes in AD patients using data from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database.ResultsIntegrative analyses identified a consistent set of miRNA alterations associated with AD. While a t-test showed a selective decrease of CSF miR-185-5p in AD versus healthy controls, logistic regression identified broader signatures in plasma (hsa-miR-125b-5p, hsa-miR-26a-5p, hsa-miR-376a-3p) and CSF (hsa-miR-499a-3p, alongside CSF hsa-miR-146a-5p, hsa-miR-16-5p, and hsa-miR-185-5p). LASSO regression further refined these to a reproducible decrease in plasma hsa-miR-125b-5p and CSF hsa-miR-185-5p, alongside an increase in plasma hsa-miR-26a-5p in AD. Together, these approaches reveal convergent miRNA dysregulation in plasma and CSF, suggesting their relevance to AD pathophysiology. Further analysis showed that lower plasma hsa-miR-125b-5p and hsa-miR-26a-5p, as well as lower CSF hsa-miR-185-5p, were associated with accelerated cognitive decline measured by ADAS13 scores. Reduced CSF hsa-miR-185-5p was significantly linked to hippocampal atrophy, with similar trends for the plasma miRNAs. Furthermore, CSF hsa-miR-185-5p levels correlated with amyloid pathology, suggesting a potential role in AD pathology.ConclusionsThese results highlight the role of CSF and plasma miRNA biomarkers in predicting cognitive and clinical decline in patients with AD.

In recent years, amyloid proteins that perform vital functions in the brain have been characterized. The question of why some amyloids are neurotoxic while others are harmless remains open. Here, we provide a brief overview of pathological and functional brain amyloids and present a comparative analysis of their amino acid sequences based on the percentage of hydrophobic and charged residues, as well as their enrichment in glutamine, asparagine, serine, and glycine. We demonstrate that pathological and functional brain amyloid proteins, along with their amyloidogenic fragments, do not differ in amino acid composition, contrary to previous assumptions. The ability of an amyloid to cause toxicity can instead be explained by the concept of “available targets”. Evidence from studies of pathological amyloids demonstrate that their toxicity is determined not only by a loss of function but also by aberrant interactions with specific targets, such as PrPC or mitochondrial membranes. Binding to these targets triggers pathological cascades that ultimately lead to cell death. In contrast, such targets are inaccessible to functional amyloids, either because of localized translation and protein sequestration within specialized cellular structures, or because their interactions with physiological partners prevent binding to dangerous targets.

ABSTRACTPreclinical detection of Alzheimer's disease (AD) is crucial to efficiently recruit clinical trial participants for examining AD‐modifying drugs and ultimately yield clinical benefits for at‐risk individuals. Cerebral amyloidosis precedes synaptic dysfunction and neurodegeneration markers, followed by the onset of AD‐related cognitive impairment. To improve early AD‐biomarker detection accuracy, patient data is, however, often collected via invasive procedures such as a lumbar puncture or intravenous injection of active radiopharmaceuticals. This coupled health risk is small yet significant and can be avoided by generating equally predictive or superior AD‐risk staging proxy biomarkers derived from noninvasive neuroimaging modalities. In addition, using neuroimaging can provide richer insights into regional distributions of brain biomarkers of AD. Motivated by that, here we train neural networks to optimally generate latent structural MRI (sMRI) representations as proxies for cerebrospinal fluid (CSF) biomarker status on multiple classification and prediction contexts, an approach that we demonstrate has the potential to be clinically useful in screening and diagnosing AD and predicting AD progression. We found that the amygdala, hippocampus, parahippocampus, posterior and middle cingulate gyrus, middle and inferior temporal gyrus, angular gyrus, precuneus, and inferior parietal lobe regions revealed maximum attribution, thereby implying the highest prognostic value for AD risk. The proposed approach of predicting amyloid and/or tau pathology biomarkers from MRI data and subsequently transferring the MRI‐derived amyloid and/or tau pathology models to predict future risk of AD progression may be useful to assist in disease screening, triage of patients for invasive testing, and efficiently determining suitability for clinical trial recruitment.

Clonally expanded CD8+ T cells may contribute to Alzheimer’s disease (AD) pathology through interactions with brain-resident cells. However, the functional impact of AD-specific T cell receptor (TCR) clonotypes remains unclear. Here, we demonstrate that CD8+ T cells undergo clonal expansion in early-stage AD mouse models, AppNL-G-F and 5xFAD, and that their depletion reduces amyloid plaque accumulation. Expanded TCR-expressing CD8+ T cells preferentially infiltrate the brain, exacerbating plaque deposition. Moreover, brain-infiltrating CD8+ T cells impair microglial transition into disease-associated states, suppressing amyloid clearance via CCL5-CCR5 signaling. Pharmacological blockade of CCL5 attenuates amyloid deposition, whereas CCL5 administration aggravates pathology. Notably, T cell depletion at later disease stages exacerbates amyloid pathology, suggesting a temporal shift in their function. Early-stage CD8+ T cells exhibit cytotoxic and effector profiles, whereas late-stage cells acquire tissue-resident and exhausted phenotypes. This temporal switch—from pathogenic to protective roles—highlights the stage-specific contribution of CD8+ T cells to AD and their potential as therapeutic targets.

BackgroundThe accumulation and propagation of α-synuclein (α-syn) are hallmark features of Parkinson’s disease (PD) and related neurodegenerative disorders. O-GlcNAcylation, an abundant post-translational modification throughout the brain, is regulated by the enzymatic activity of the cycling enzymes O-GlcNAc transferase (OGT) and O-GlcNAcase (OGA) and has been implicated in altering α-syn toxicity. Nevertheless, the interplay between modulating O-GlcNAc cycling and α-syn aggregation and the propagation of amyloid pathology is not well elucidated.MethodsTo this end, we delivered conformational strains of α-syn in the striatum of mice or neuronal and microglial co-cultured cells following pharmacologically or genetically inhibited OGT and OGA. The substantia nigra was injected with an adeno-associated viral vector coding for α-syn combined with α-syn preformed fibrils to examine α-syn-induced dopaminergic cytotoxicity. The α-syn pathology and spreading, protein O-GlcNAcylation, OGT and OGA levels, microglial inflammation, and behavioral impairments were evaluated. Furthermore, the O-GlcNAc modification and proteolysis status of α-syn under O-GlcNAc cycling modification were also assessed using a combination of approaches, including Click-iT™ O-GlcNAc enzyme labeling, sWGA pulldown, HPLC-MS/MS, and immunohistochemical analysis following proteasome and autophagy-lysosome inhibition.ResultsWe found that modulation of O-GlcNAc cycling, governed by the two enzymes OGT and OGA, significantly affected α-syn aggregation, propagation, dopaminergic neuronal degeneration, and microglial inflammation. Pathological α-syn transmission to adjacent cells and anatomically connected brain regions was found to suppress recipient cellular O-GlcNAc levels, concomitant with reduced OGT expression. Pharmacological inhibition or genetic knockdown of OGT exacerbated α-syn aggregation, enhanced its intercellular transmission, and intensified NOD-, LRR-, and pyrin domain-containing 3 (NLRP3)-mediated microglial inflammation. Conversely, increasing O-GlcNAcylation via OGA inhibition ameliorated these pathological processes. Furthermore, we demonstrate that enzymatic O-GlcNAcylation significantly regulates the aggregation of fibril-induced initial dimer formation and facilitates the clearance of α-syn aggregates through autophagosome-lysosome flux.ConclusionsThese findings highlight the critical regulatory role of O-GlcNAc modification in α-syn pathology and conformational strain formation, and provide mechanical evidence that enhancing O-GlcNAc modifications alleviates pathological α-syn proteolysis by restoring autophagosome-lysosome flux.Supplementary InformationThe online version contains supplementary material available at 10.1186/s13024-025-00904-2.

Alzheimer's disease (AD) and epilepsy (EP) share a complex bidirectional relationship, yet the molecular mechanisms underlying their comorbidity remain insufficiently explored. To identify potential transcriptional programs across animal models and human patients with AD and EP, we conducted a comprehensive genome-wide transcriptomic analysis. Our investigation included mouse models of temporal lobe epilepsy (pilocarpine- and kainic acid-induced; n = 280), AD transgenic models (7 transgenic models expressing human tau or amyloid pathology; n = 257), and performed cross-species validation in human cohorts (EP: n = 182; AD: n = 301). We identified a highly conserved immune-related module across all models and patient cohorts. The hub consensus signatures of this module were centered around a microglial synaptic pruning pathway involving TYROBP, TREM2, and C1Q complement components. Gene regulatory network analysis identified TYROBP as the key regulatory signature. These signatures showed consistent up-regulation in both conditions and diagnostic potential. Differential expression analyses revealed their predominant expression in specific microglial subpopulations associated with complement-mediated synaptic pruning and immune activation. Neural circuit modeling further demonstrates the asymmetric sensitivity of synaptic pruning to network dynamics. Loss of inhibitory synapses has a disproportionately significant impact on neural network excitation/inhibition balance and synchronization. Our findings support microglial complement-mediated synaptic pruning as a conserved central pathway linking neurodegeneration to epileptogenesis, suggesting a promising therapeutic target for AD and EP comorbidity.

Association of thyroid autoimmune status with Alzheimer's disease biomarkers in euthyroid subjects.

Pathological amyloids, like those formed by α-synuclein in Parkinson's disease, are recently found to catalyze the hydrolysis of model substrates in vitro. Here it is reported that the universal energy molecule ATP is another substrate for α-synuclein amyloid chemical catalysis. To reveal the underlying mechanism, the high-resolution cryo-EM structure of the amyloids in the presence of ATP is solved. The structure reveals a type 1A amyloid fold with an additional β-strand involving residues 16-22 that wraps around the ATP, creating an enclosed cavity at the interface of the protofilaments. Mutations of putative ATP-interacting residues in the cavity and the additional β-strand showed that replacing any one of Lys21, Lys23, Lys43, Lys45, and Lys60 with Ala reduced amyloid-mediated ATPase activity. High-resolution structural analysis of Lys21Ala α-synuclein amyloids in the presence of ATP reveals the same fold as wild-type α-synuclein amyloids but without the extra β-strand and with ATP oriented differently. It is concluded that positively-charged side chains, along with ordering of the N-terminal part into a β-strand, enclosing the cavity, are essential parameters governing ATP hydrolysis by α-synuclein amyloids. Amyloid-catalyzed ATP hydrolysis may hamper ATP-dependent rescue systems near amyloid deposits in vivo.

<p> Introduction: Alzheimer's disease (AD) is a neurodegenerative disorder characterized by synaptic dysfunction and the accumulation of amyloid plaques. The molecular mechanisms linking gene dysregulation, pathogenic variants, and protein interaction networks to these core pathologies remain incompletely understood. This study aimed to integrate transcriptomic data with mutation and structural modeling to uncover disease mechanisms and identify therapeutic targets. </p><p> Methods: We performed differential gene expression analysis on the GSE138260 microarray dataset using GEO2R to identify DEGs in AD brain tissue. Missense mutations in DEGs were retrieved from the Alzheimer's Disease Variant Portal (ADVP). Protein-protein interaction networks were constructed using the STRING database to identify connections with the amyloid precursor protein (APP). Molecular dynamics simulations were conducted to evaluate the structural consequences of the BDNF V66M mutation. </p><p> Results: A total of 1,588 DEGs were identified, including upregulation of immune-related genes and downregulation of neuroplasticity-associated genes (e.g., BDNF, GRIN2B, GRM8). PPI analysis revealed a core network centered on APP, including BDNF as a direct interactor. The V66M variant in BDNF, confirmed to be downregulated in AD brains, showed increased rigidity and localized flexibility in structural models. </p><p> Discussion: The integration of transcriptomics and protein modeling revealed a critical link between BDNF dysfunction and APP interaction in AD. The V66M mutation was found to structurally alter BDNF, potentially disrupting its neuroprotective roles. The findings suggested that impaired BDNF signaling, driven by transcriptional repression and structural mutation, contributes to amyloid pathology and synaptic failure. </p><p> Conclusion: This multi-omics investigation has identified BDNF as a converging point of gene dysregulation and pathogenic mutation within an APP-centric network. Structural alterations induced by the V66M mutation may exacerbate amyloid accumulation and neuronal dysfunction, supporting therapeutic strategies aimed at enhancing BDNF signaling in AD.

Metal ions control amyloid catalysis.

Accumulation of amyloid plaque drives pathogenesis of Alzheimer disease (AD). Reduction of amyloid via amyloid-targeting therapies may result in clinical benefit. To assess the correlation of posttreatment amyloid levels with clinical outcomes and biomarkers in AD. This was a post hoc exploratory analysis from the randomized, placebo-controlled phase 3 trial, TRAILBLAZER-ALZ 2, conducted June 2020 through April 2023 at 277 medical research centers/hospitals in 8 countries. A total of 8240 participants aged 60 to 85 years with early symptomatic AD with amyloid and tau pathology based on positron emission tomography (PET) imaging were assessed for eligibility. Of these, 6504 participants were excluded predominantly due to inadequate amyloid or tau pathology. The current analysis included 1582 participants (766 in the donanemab group and 816 in the placebo group) with baseline and at least 1 posttreatment assessment. Data analysis took place from July 2024 to March 2025. Participants were randomized 1:1 to receive donanemab (700 mg for the first 3 doses and 1400 mg thereafter) or placebo intravenously every 4 weeks for up to 72 weeks, with outcomes assessed through 76 weeks. Participants were categorized into 1 of 10 groups (deciles) based on their lowest amyloid value observed posttreatment. Clinical progression was assessed via changes in integrated Alzheimer's Disease Rating Scale (iADRS) and Clinical Dementia Rating-Sum of Boxes (CDR-SB) scores. Plasma biomarkers measured included phosphorylated tau 217 (p-tau217), p-tau181, glial fibrillary acidic protein (GFAP), and neurofilament light chain (NfL). Correlations between the median amyloid level in each decile were assessed with 76-week least-squares mean changes in each outcome and biomarker. Analyses included 1582 participants, including 766 treated with donanemab and 816 with placebo. The mean (SD) age was 72.9 (6.2) years, and 900 participants (56.9%) were female. Participants who received donanemab had lower posttreatment amyloid values than those in the placebo group. Across the trial population, lower posttreatment amyloid levels were correlated with slower clinical progression as measured by iADRS score (R2, 0.73 [95% CI, 0.37-0.97]) and CDR-SB score (R2, 0.87 [95% CI, 0.70-0.97]) and with decreases in p-tau217 (R2, 0.86 [95% CI, 0.73-0.97]), p-tau181 (R2, 0.88 [95% CI, 0.77-0.97]), and GFAP (R2, 0.87 [95% CI, 0.76-0.97]). There was no correlation between posttreatment amyloid value and NfL (R2, 0.03 [95% CI, 0.00-0.54]). The findings in this secondary analysis of a randomized clinical trial demonstrating a correlation between posttreatment amyloid plaque level and clinical benefit support amyloid plaque removal as the mechanism of action for donanemab treatment and the level of amyloid plaque as a potential surrogate biomarker in amyloid-targeting therapies. ClinicalTrials.gov Identifier: NCT04437511.

Biophysical analysis of angiotensin II and amyloid-β cross-interaction in aggregation and membrane disruption.

BackgroundSynapse loss is linked to cognitive symptoms in Alzheimer’s Disease (AD) and Cerebrospinal fluid (CSF) synaptic biomarkers may clarify disease heterogeneity and disease mechanisms for progression beyond amyloid (Aβ) and tau pathologies, potentially revealing new drug targets.MethodsWe used a mass-spectrometry panel of 17 synaptic biomarkers including neuronal pentraxins (NPTXs) linked to glutamatergic signaling, and 14-3-3 proteins linked to tau-pathology and synaptic plasticity. Synapse markers were evaluated in two independent cohorts: Dementia Disease Initiation (DDI) (n = 346) and Amsterdam Dementia Cohort (n = 397), both with cognitive assessments up to 10 years. We used linear regression to compare synapse marker differences between CSF-determined Aβ + cognitively normal (CN) and Mild Cognitive Impairment (MCI) groups, with or without CSF tau pathology (Tau+/-), relative to CN Aβ-/Tau- controls; and associations between synapse markers and medial temporal lobe (MTL) MRI volumetrics in the DDI cohort and with verbal memory in both cohorts. A funneling procedure identified proteins related to Aβ/Tau pathology and memory impairment in both cohorts, which were used to evaluate relations to Aβ/Tau biological progression in the DDI cohort and memory decline in both cohorts. Finally, we explored genetic pathways associated with these synaptic proteins.ResultsIn both cohorts, most markers were elevated in Aβ+/Tau + cases compared to controls, particularly 14-3-3ζ/δ. Several proteins were reduced in Aβ+/Tau- cases, especially NPTX-2, while 14-3-3ζ/δ remained elevated. However, the increase in e.g. 14-3-3ζ/δ and reduction in e.g. NPTX2 were more pronounced in patients with MCI than CN cases regardless of tau-pathology, corresponding to verbal memory impairment and MTL atrophy. Elevated baseline 14-3-3ζ/δ and rab GDP Dissociation Inhibitor Alpha (GDI-1) associated with future progression from Aβ+/Tau- to Aβ+/Tau+. Significant associations (all p < 0.001) were found between 14-3-3 protein genes (YWHAZ, YWHAE) and pathways linked to AD, including the p38 MAPK, IGF, PIK3/AKT and between GDI1 and p38 MAPK upstream pathway (p < 0.05) all connected to synaptic plasticity. Correspondingly, a robust 14-3-3ζ/δ association with future memory decline was observed in both cohorts.ConclusionsReduced markers for excitatory signaling in Aβ+/Tau- and increased synaptic plasticity markers in Aβ+/Tau + cases suggest differential but linked processes underlying disease progression and resilience in the groups.Supplementary InformationThe online version contains supplementary material available at 10.1186/s13024-025-00899-w.

BackgroundSmaller midbrain volumes predict Alzheimer’s Disease (AD) progression and faster conversion from Mild Cognitive Impairment (MCI) to dementia. Along with this, various midbrain-target areas are characterized by neuroinflammation since the MCI stage. The concomitance of neuroinflammation, Αβ and tau appears to be a strong predictor for conversion from MCI to dementia.Yet, how midbrain degeneration could cause disease progression, and what mechanisms are involved in triggering neuroinflammation in midbrain-target areas such as the hippocampus remain unexplored.MethodsUsing adult C57BL/6N mice we generated a new mouse model carrying lesions in three midbrain nuclei, the dopaminergic Ventral Tegmental Area (VTA) and Substantia Nigra pars compacta (SNpc) and the serotonergic Interpeduncular Nucleus (IPN), to evaluate the consequences of dopamine and serotonin deprivation in midbrain-target areas. We characterized this model by performing stereological cell counts, analysis of monoaminergic fibers, monoamine levels, electrophysiology and behavioral tests. We then assessed hippocampal neuroinflammation by analyzing glia cell count, changes in morphology, NLRP3 inflammasome activation and cytokine levels, and microglia transcriptional profiling. In a separate set of experiments, we induced experimental midbrain lesion in Tg2576 transgenic mice overexpressing the Swedish mutant amyloid precursor protein, to evaluate the effect of monoamine deprivation on the hippocampus in concomitance with amyloid-β (Aβ) accumulation. The lesion performed in Tg2576 mice, as opposed to that in C57BL/6N mice, provides valuable insights into how neuroinflammation is influenced by Aβ accumulation versus the exclusive impact of impaired monoaminergic signaling.ResultsThe concomitant depletion of dopaminergic and serotonergic inputs within the hippocampus of C57BL/6N mice provokes a pronounced activation of microglia via the NLRP3-inflammasome pathway, accompanied by increased IL-1β expression. Pharmacological intervention with either dopaminergic (L-DOPA or A68930) or serotonergic (fluoxetine) agents abrogates this neuroinflammatory response. In the Tg2576 transgenic mouse model of amyloid pathology, which exhibits progressive Aβ deposition, superimposed midbrain degeneration markedly amplifies AD-like neuropathology. This includes exacerbation of microglial reactivity, robust astrocyte response, precocious Aβ plaque burden, and induction of pathological tau hyperphosphorylation. Notably, administration of L-DOPA or fluoxetine significantly attenuates both the astrocyte reactivity and tau hyperphosphorylation in the lesioned Tg2576 cohort.ConclusionsThese results highlight the pivotal role of midbrain damage for the amplification of neuroinflammatory cascades and AD pathology. Moreover, they offer mechanistic insight into the faster progression to dementia in patients with midbrain deficits. By translating these findings into clinical practice, we can advance towards a precision medicine approach in disease management.Supplementary InformationThe online version contains supplementary material available at 10.1186/s13024-025-00893-2.