The Potential Role of Neurogranin in Alzheimer’s Disease

Journal of Integrative Neuroscience, Год журнала: 2025, Номер 24(3)

Опубликована: Март 20, 2025

Alzheimer's disease (AD) is the most common form of dementia and characterized by excessive deposition amyloid-β (Aβ) plaques formation neurofibrillary tangles. Numerous new studies also indicate that synaptic damage loss play crucial roles in AD basis cognitive impairment. In recent years, synaptic-related proteins have emerged as important biomarkers for early diagnosis AD. Among these proteins, neurogranin (Ng), a postsynaptic protein widely present dendritic spines associative cortex brain, plays significant role memory, learning, plasticity, long-term potentiation (LTP). This review aims to reveal link between Ng AD, well potential prediction development disease, identification therapeutic target

Язык: Английский

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A cerebrospinal fluid synaptic protein biomarker for prediction of cognitive resilience versus decline in Alzheimer’s disease

Nature Medicine, Год журнала: 2025, Номер unknown

Опубликована: Март 31, 2025

Rates of cognitive decline in Alzheimer's disease (AD) are extremely heterogeneous. Although biomarkers for amyloid-beta (Aβ) and tau proteins, the hallmark AD pathologies, have improved pathology-based diagnosis, they explain only 20-40% variance AD-related impairment (CI). To discover novel CI AD, we performed cerebrospinal fluid (CSF) proteomics on 3,397 individuals from six major prospective case-control cohorts. Synapse proteins emerged as strongest correlates CI, independent Aβ tau. Using machine learning, derived CSF YWHAG:NPTX2 synapse protein ratio, which explained 27% beyond pTau181:Aβ42, 11% positron emission tomography, 28% neurofilament, growth-associated 43 neurogranin Aβ+ phosphorylated tau+ (A+T1+) individuals. also increased with normal aging 20 years before estimated symptom onset carriers autosomal dominant mutations. Regarding prognosis, predicted conversion A+T1+ cognitively to mild (standard deviation increase hazard ratio = 3.0, P 7.0 × 10-4) dementia 2.2, 8.2 10-16) over a 15-year follow-up, adjusting neurogranin, 43, age, APOE4 sex. We developed plasma proteomic signature evaluated 13,401 samples, partly recapitulated YWHAG:NPTX2. Overall, our findings underscore robust prognostic biomarker resilience versus progression, highlight potential replacing measurement further implicate dysfunction core driver dementia.

Язык: Английский

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Associations between fluid biomarkers and PET imaging ([11C]UCB-J) of synaptic pathology in Alzheimer's disease

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2025, Номер unknown

Опубликована: Апрель 5, 2025

Positron Emission Tomography (PET) imaging with ligands for synaptic vesicle glycoprotein 2A (SV2A) has emerged as a promising methodology measuring density in Alzheimer's disease (AD). We investigate the relationship between SV2A PET and CSF protein changes of AD patients. Twenty-one participants early 7 cognitively normal (CN) individuals underwent [ 11 C]UCB-J PET. used mass spectrometry to measure panel proteins CSF. In group, higher levels syntaxin-7 PEBP-1 were associated lower global density. total sample, was AP2B1, neurogranin, γ-synuclein, GDI-1, PEBP-1, syntaxin-1B, but not neuronal pentraxins or 14-3-3 zeta/delta. Reductions found compared CN using observed be biomarker proteins.

Язык: Английский

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Novel CSF β-synuclein-specific assays signal early synaptic degeneration in Alzheimer’s disease

Alzheimer s Research & Therapy, Год журнала: 2025, Номер 17(1)

Опубликована: Апрель 14, 2025

Язык: Английский

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Cerebrospinal fluid synaptic biomarker changes in bipolar disorder – A longitudinal case-control study

Journal of Affective Disorders, Год журнала: 2024, Номер 358, С. 250 - 259

Опубликована: Май 7, 2024

This exploratory study investigated cerebrospinal fluid (CSF) synaptic protein biomarkers in bipolar disorder (BD), aiming to highlight the neurobiological basis of disorder. With shared cognitive impairment features between BD and Alzheimer's disease, considering increased dementia risk patients, explores potential connections. Fifty-nine well-characterized patients with thirty-seven healthy control individuals were examined followed for one year. Synaptic proteins encompassing neuronal pentraxins (NPTX)1, NPTX2, NPTX-receptor, 14–3-3 family epsilon, zeta/delta, activating protein-2 complex subunit beta, synucleins beta-synuclein gamma-synuclein, complexin-2, phosphatidylethanolamine-binding 1, rab GDP dissociation inhibitor alpha, syntaxins 1B 7 measured CSF using a microflow liquid chromatography-mass spectrometric multiple reaction monitoring set-up. Biomarker levels compared HC before, during, after mood episodes. The revealed no statistically significant differences HC, neither at baseline, one-year follow-up, or terms changes from baseline follow-up. Moreover, unaltered when they stabilized euthymia following an affective episode It is uncertain what biomarker concentrations reflect since we yet do not know mechanisms release these proteins, are decreased reflect. first-ever investigation panel dysfunction found cross-sectionally longitudinally.

Язык: Английский

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Decoding Behavior: Utilizing Virtual Reality Digital Marker and Machine Learning for Early Detection of Mild Cognitive Impairment

Опубликована: Май 11, 2024

The imperative for early mild cognitive impairment (MCI) detection is underscored by the limitations of traditional biomarkers, high cost and invasiveness, they often fail to capture behavioral changes in MCI patients associated with impaired instrumental activities daily living (IADL). This study introduces a cost-effective, non-invasive alternative using digital markers, "virtual kiosk test", which involves performing IADL tasks such as ordering food via virtual reality (VR) detect at an stage. Involving 20 healthy controls 31 patients, four key features within VR markers effectively differentiate groups: hand movement speed, proportion fixation duration, time completion, number errors. A machine learning model demonstrated effectiveness 93.3% accuracy, 100% sensitivity, 83.3% specificity, 90% precision, 94.7% F1-score group differentiation. Findings suggest that observing behaviors test 5 minutes can be efficient approach detection, acting reliable markers.

Язык: Английский

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TauP301L disengages from the proteosome core complex and neurogranin coincident with enhanced neuronal network excitability

Cell Death and Disease, Год журнала: 2024, Номер 15(6)

Опубликована: Июнь 18, 2024

Abstract Tauopathies are characterised by the pathological accumulation of misfolded tau. The emerging view is that toxic tau species drive synaptic dysfunction and potentially propagation before measurable neurodegeneration evident, but underlying molecular events not well defined. Human non-mutated 0N4R (tau WT ) P301L mutant were expressed in mouse primary cortical neurons using adeno-associated viruses to monitor early changes function onset neuronal loss. In this model was differentially phosphorylated relative wt with a notable increase phosphorylation at ser262. Affinity purification - mass spectrometry combined tandem tagging used quantitatively compare interactomes. This revealed an enrichment ribosomal proteins decreased interaction proteasome core complex reduced degradation. Differences members key calcium-calmodulin signalling pathway also identified, most notably, increased association CaMKII calcineurin candidate AD biomarker neurogranin. Decreased neurogranin corresponded appearance enhanced levels extracellular suggestive potential release or leakage from synapses. Finally, analysis network activity micro-electrode arrays showed overexpression promoted basal hyperexcitability coincident these interactome implicating specific alterations function.

Язык: Английский

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CSF proteomic profiles of neurodegeneration biomarkers in Alzheimer's disease

Alzheimer s & Dementia, Год журнала: 2024, Номер 20(9), С. 6205 - 6220

Опубликована: Июль 6, 2024

Abstract INTRODUCTION We aimed to unravel the underlying pathophysiology of neurodegeneration (N) markers neurogranin (Ng), neurofilament light (NfL), and hippocampal volume (HCV), in Alzheimer's disease (AD) using cerebrospinal fluid (CSF) proteomics. METHODS Individuals without dementia were classified as A+ (CSF amyloid beta [Aβ]42), T+ phosphorylated tau181), N+ or N− based on Ng, NfL, HCV separately. CSF proteomics generated compared between groups analysis covariance. RESULTS Only a few individuals A+T+Ng−. A+T+Ng+ A+T+NfL+ showed different proteomic profiles A+T+Ng− A+T+NfL−, respectively. Both Ng+ NfL+ associated with neuroplasticity, though opposite directions. Compared A+T+HCV−, A+T+HCV+ changes, oxidative stress. DISCUSSION Different N are distinct neurodegenerative processes should not be equated. may differentially complement staging beyond tau. Our findings suggest that Ng an optimal marker, given its low incongruency tau pathophysiology. Highlights In disease, (Ng)+, (NfL)+, (HCV)+ differential protein expression fluid. although HCV+ related Neurodegeneration refine might it relates more closely

Язык: Английский

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β-Synuclein as a candidate blood biomarker for synaptic degeneration in Alzheimer’s disease

Alzheimer s Research & Therapy, Год журнала: 2022, Номер 14(1)

Опубликована: Ноя. 30, 2022

Synaptic degeneration is an early event closely associated with the course of Alzheimer's disease (AD). The identification synaptic blood biomarkers is, therefore, great interest and clinical relevance. levels most proteins are increased in cerebrospinal fluid (CSF) patients AD, but their detection hitherto either unavailable or not very informative. This paradigm related to low concentration, peripheral origin, presence highly abundant that hinder detection. In recent years, significant progress has been made detecting presynaptic protein β-synuclein. mini-review summarizes results highlight role β-synuclein as a candidate marker for AD.

Язык: Английский

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Evaluation of cerebrospinal fluid levels of synaptic vesicle protein, VAMP-2, across the sporadic Alzheimer’s disease continuum

Alzheimer s Research & Therapy, Год журнала: 2023, Номер 15(1)

Опубликована: Окт. 28, 2023

Abstract Background Synapse loss is an early event that precedes neuronal death and symptom onset considered the best neuropathological correlate of cognitive decline in Alzheimer’s disease (AD). Vesicle-associated membrane protein 2 (VAMP-2) has emerged as a promising biomarker AD-related synapse degeneration cerebrospinal fluid (CSF). The aim this study was to explore CSF profile VAMP-2 across AD continuum relation core biomarkers, other synaptic proteins, neurogranin (Ng) synaptosomal-associated Protein-25 kDa (SNAP-25) performance. Methods We developed digital immunoassay on Single Molecule Array platform quantify used existing immunoassays Ng, SNAP-25 biomarkers. clinical included 62 cognitively unimpaired biomarker-negative subjects 152 participants from SPIN cohort (Sant Pau Initiative Neurodegeneration). Cognitive measures episodic, semantic, executive visuospatial domains global cognition were included. Statistical methods χ tests, spearman correlation, ANCOVA analyses. Results assay had good analytical performance (repeatability 8.9%, intermediate precision 10.3%). Assay antibodies detected native human brain homogenates. concentrations VAMP-2, lower preclinical stage 1 compared controls higher at later stages associated with particularly total tau (adj. r = 0.62 0.78, p < 0.001). All three proteins all individuals 0.04 0.19, 0.05). Conclusions Our novel accurately changes CSF, which reflect biomarkers multiple domains.

Язык: Английский

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