Dense core vesicle markers in CSF and cortical tissues of patients with Alzheimer’s disease

Barranco, Neus; Plá, Virginia; Alcolea, Daniel; Sánchez-Domínguez, Irene; Fischer‐Colbrie, Reiner; Ferrer, Isidró; Lleó, Alberto; Aguado, Fernando

doi:10.1186/s40035-021-00263-0

Cited by 13 publications

(11 citation statements)

References 92 publications

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“…Chronic neuronal inactivity also blocked DCV release and resulted in DCVs accumulation in the pre-synapse [ 73 ]. The failure in DCV release in AD is consistent with previous observation of aberrant accumulation of DCV proteins in dystrophic neurites, degenerative structures originated from axons [ 35 , 52 , 82 ] and decreased DCV proteins in the CSF as a potential biomarker for AD [ 5 ]. Because proper DCV release is important for peptidergic transmission which controls circuitry function and homeostasis [ 24 ], our finding suggests that alterations in peptidergic transmission is likely involved in AD.…”

Section: Discussionsupporting

confidence: 90%

Damaged mitochondria coincide with presynaptic vesicle loss and abnormalities in alzheimer’s disease brain

Wang

Zhao

et al. 2023

acta neuropathol commun

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Loss of synapses is the most robust pathological correlate of Alzheimer’s disease (AD)-associated cognitive deficits, although the underlying mechanism remains incompletely understood. Synaptic terminals have abundant mitochondria which play an indispensable role in synaptic function through ATP provision and calcium buffering. Mitochondrial dysfunction is an early and prominent feature in AD which could contribute to synaptic deficits. Here, using electron microscopy, we examined synapses with a focus on mitochondrial deficits in presynaptic axonal terminals and dendritic spines in cortical biopsy samples from clinically diagnosed AD and age-matched non-AD control patients. Synaptic vesicle density within the presynaptic axon terminals was significantly decreased in AD cases which appeared largely due to significantly decreased reserve pool, but there were significantly more presynaptic axons containing enlarged synaptic vesicles or dense core vesicles in AD. Importantly, there was reduced number of mitochondria along with significantly increased damaged mitochondria in the presynapse of AD which correlated with changes in SV density. Mitochondria in the post-synaptic dendritic spines were also enlarged and damaged in the AD biopsy samples. This study provided evidence of presynaptic vesicle loss as synaptic deficits in AD and suggested that mitochondrial dysfunction in both pre- and post-synaptic compartments contribute to synaptic deficits in AD.

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Section: Discussionsupporting

confidence: 90%

Damaged mitochondria coincide with presynaptic vesicle loss and abnormalities in alzheimer’s disease brain

Wang

Zhao

et al. 2023

acta neuropathol commun

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“…In the tauopathy brain, GVBs [ 17 , 19 – 23 ] and putative GVBs [ 3 , 13 – 15 , 24 , 25 ] are occasionally observed in neurons without apparent tau pathology. Based on semiquantitative visual assessment, previous studies have reported a range of 5–25% [ 13 – 15 , 17 , 20 ] up to even 80% [ 25 ] of GVB+ neurons without pathological tau. In the current study, we performed systematic analysis of pathological tau at the single-cell level.…”

Section: Discussionmentioning

confidence: 99%

“…The strong evidence that connects tau pathology and GVBs is challenged by studies reporting the presence of GVBs [17,[19][20][21][22][23] and putative GVBs for which CK1δ positivity was not demonstrated [3, 13-15, 24, 25] in neurons lacking signal for pathological tau markers (tau−) in the human tauopathy brain. Additionally, the presence of GVBs has also been associated with α-synucleinopathies including Parkinson's disease (PD) [11,[26][27][28][29][30], PD with dementia [4,28,31] and multiple system atrophy (MSA) [4,30,32].…”

Section: Introductionmentioning

confidence: 99%

Granulovacuolar degeneration bodies are independently induced by tau and α-synuclein pathology

et al. 2022

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Background Granulovacuolar degeneration bodies (GVBs) are intracellular vesicular structures that commonly accompany pathological tau accumulations in neurons of patients with tauopathies. Recently, we developed the first model for GVBs in primary neurons, that requires exogenous tau seeds to elicit tau aggregation. This model allowed the identification of GVBs as proteolytically active lysosomes induced by tau pathology. GVBs selectively accumulate cargo in a dense core, that shows differential and inconsistent immunopositivity for (phosphorylated) tau epitopes. Despite the strong evidence connecting GVBs to tau pathology, these structures have been reported in neurons without apparent pathology in brain tissue of tauopathy patients. Additionally, GVBs and putative GVBs have also been reported in the brain of patients with non-tau proteinopathies. Here, we investigated the connection between pathological protein assemblies and GVBs in more detail. Methods This study combined newly developed primary neuron models for tau and α-synuclein pathology with observations in human brain tissue from tauopathy and Parkinson’s disease patients. Immunolabeling and imaging techniques were employed for extensive characterisation of pathological proteins and GVBs. Quantitative data were obtained by high-content automated microscopy as well as single-cell analysis of confocal images. Results Employing a novel seed-independent neuronal tau/GVB model, we show that in the context of tauopathy, GVBs are inseparably associated with the presence of cytosolic pathological tau and that intracellular tau aggregation precedes GVB formation, strengthening the causal relationship between pathological accumulation of tau and GVBs. We also report that GVBs are inseparably associated with pathological tau at the single-cell level in the hippocampus of tauopathy patients. Paradoxically, we demonstrate the presence of GVBs in the substantia nigra of Parkinson’s disease patients and in a primary neuron model for α-synuclein pathology. GVBs in this newly developed α-synuclein/GVB model are induced in the absence of cytosolic pathological tau accumulations. GVBs in the context of tau or α-synuclein pathology showed similar immunoreactivity for different phosphorylated tau epitopes. The phosphorylated tau immunoreactivity signature of GVBs is therefore independent of the presence of cytosolic tau pathology. Conclusion Our data identify the emergence of GVBs as a more generalised response to cytosolic protein pathology.

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“…Next, we repeated the module visualization, cell-type specific differential gene expression, and SCG2, SCG3, SCG5, CHGA, and CHGB encode for neuropeptides precursors/neuropeptides secretogranin II, Secretogranin III, 7B2, chromogranin A (CGA), and chromogranin B (CGB) that will be proteolytically processed into neuropeptides in the chromogranin-secretogranin family (75). These peptides are major constituents of and often markers of dense core vesicles (DCV) that store neuropeptides (76). Our finding signifies that the disruption of NP signaling in AD is likely widespread (e.g., not limited to a couple of NPs).…”

Section: Decreased Np Cell Population In Ad Entorhinal Cortexmentioning

confidence: 99%

Single-cell sequencing of Entorhinal Cortex Reveals Wide-Spread Disruption of Neuropeptide Networks in Alzheimer’s Disease

Larsen

2022

Preprint

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Alzheimer’s disease (AD) is a fatal neurodegenerative disease that involves early and significant neuropathological changes within the entorhinal cortex (EC). Many have reported on neuronal loss and synaptic dysfunction in the brains of AD patients and AD models. In parallel, abnormalities of neuropeptides (NPs) that play important roles in modulating neuronal activities are commonly observed in AD and other neurodegenerative diseases. However, the involvement of NPs has mostly been studied in the context of neurons; a cell type-specific examination of NP expression in AD brains is needed. Here, we aim to examine the NP networks in the EC of AD brains using single-nuclei and bulk transcriptomic data from other regions in the temporal cortex, focusing on the gene expression of NP and their cognate G-protein coupled receptors. We find that NP genes were expressed by all major cell types in the brain and there was a significant decrease in the quantity and the proportion of cells that express NPs in AD EC cells. On the contrary, the overall expression of GPCR genes showed an increase in AD cells, likely reflecting ongoing compensatory mechanisms in AD brains. In addition, we report that there was a disproportionate absence of cells expressing higher levels and greater diversity of NPs in AD brains. Finally, we established a negative correlation between age and the abundance of AD-associated NPs in the hippocampus, supporting that the disruption of the NP signaling network in the EC may contribute to the early pathogenesis of AD. In short, we report widespread disruption of the NP networks in AD brains at the single-cell level. In light of our results, we hypothesize that brain cells, especially neurons, that express high levels of NPs may exhibit selective vulnerability to AD. Moreover, it is likely AD brains undergo specific adaptive changes to fluctuating NP signaling, a process that can likely be targeted with therapeutic approaches aimed at stabilizing NP expression landscapes. Given that GPCRs are one of the most druggable targets for neurological diseases and disorders, we believe NP signaling pathways can be harnessed for future biomarkers and treatment strategies for AD.

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Dense core vesicle markers in CSF and cortical tissues of patients with Alzheimer’s disease

Cited by 13 publications

References 92 publications

Damaged mitochondria coincide with presynaptic vesicle loss and abnormalities in alzheimer’s disease brain

Damaged mitochondria coincide with presynaptic vesicle loss and abnormalities in alzheimer’s disease brain

Granulovacuolar degeneration bodies are independently induced by tau and α-synuclein pathology

Single-cell sequencing of Entorhinal Cortex Reveals Wide-Spread Disruption of Neuropeptide Networks in Alzheimer’s Disease

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