Contribution of Neurons and Glial Cells to Complement-Mediated Synapse Removal during Development, Aging and in Alzheimer’s Disease

Luchena, Celia; Zuazo-Ibarra, Jone; Alberdi, Elena; Matute, Carlos; Capetillo-Zárate, Estibaliz

doi:10.1155/2018/2530414

Cited by 62 publications

(60 citation statements)

References 124 publications

(177 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In aggregate, aberrant activation of neuroinflammatory signaling mechanisms during adolescence might be crucial for excessive spine pruning in schizophrenia [21,68], and re-activation with advanced aging might drive neurodegenerative pathology [16,[18][19][20], contributing to synaptic and cognitive dysfunction in diseases. The current data add to this emerging field, suggesting that complement activation within pyramidal cells might contribute to the atrophy of higher cognitive circuits and increases naturally with age [16,69].…”

Section: Implications For Neurological and Psychiatric Diseasementioning

confidence: 61%

Classical complement cascade initiating C1q protein within neurons in the aged rhesus macaque dorsolateral prefrontal cortex

Datta

Leslie

Morozov

et al. 2020

J Neuroinflammation

View full text Add to dashboard Cite

Background: Cognitive impairment in schizophrenia, aging, and Alzheimer's disease is associated with spine and synapse loss from the dorsolateral prefrontal cortex (dlPFC) layer III. Complement cascade signaling is critical in driving spine loss and disease pathogenesis. Complement signaling is initiated by C1q, which tags synapses for elimination. C1q is thought to be expressed predominately by microglia, but its expression in primate dlPFC has never been examined. The current study assayed C1q levels in aging primate dlPFC and rat medial PFC (mPFC) and used immunoelectron microscopy (immunoEM), immunoblotting, and co-immunoprecipitation (co-IP) to reveal the precise anatomical distribution and interactions of C1q. Methods: Age-related changes in C1q levels in rhesus macaque dlPFC and rat mPFC were examined using immunoblotting. High-spatial resolution immunoEM was used to interrogate the subcellular localization of C1q in aged macaque layer III dlPFC and aged rat layer III mPFC. co-IP techniques quantified protein-protein interactions for C1q and proteins associated with excitatory and inhibitory synapses in macaque dlPFC. Results: C1q levels were markedly increased in the aged macaque dlPFC. Ultrastructural localization found the expected C1q localization in glia, including those ensheathing synapses, but also revealed extensive localization within neurons. C1q was found near synapses, within terminals and in spines, but was also observed in dendrites, often near abnormal mitochondria. Similar analyses in aging rat mPFC corroborated the findings in rhesus macaques. C1q protein increasingly associated with PSD95 with age in macaque, consistent with its synaptic localization as evidenced by EM. Conclusions: These findings reveal novel, intra-neuronal distribution patterns for C1q in the aging primate cortex, including evidence of C1q in dendrites. They suggest that age-related changes in the dlPFC may increase C1q expression and synaptic tagging for glial phagocytosis, a possible mechanism for age-related degeneration.

show abstract

Section: Implications For Neurological and Psychiatric Diseasementioning

confidence: 61%

Classical complement cascade initiating C1q protein within neurons in the aged rhesus macaque dorsolateral prefrontal cortex

Datta

Leslie

Morozov

et al. 2020

J Neuroinflammation

View full text Add to dashboard Cite

show abstract

“…Here, we report a correlation between CHI3L1 and C1q protein levels in early AD. C1q is the first component of the complement pathway [90], and microglia and astrocytes are sources of C1q in the AD brain [91,92]. Complement-associated factors are implicated in pathogen presentation, neurodegeneration, and microglia resolution of tissue injury [93].…”

Section: Discussionmentioning

confidence: 99%

Frontal cortex chitinase and pentraxin neuroinflammatory alterations during the progression of Alzheimer’s disease

Moreno‐Rodríguez

Perez

Nadeem

et al. 2020

J Neuroinflammation

View full text Add to dashboard Cite

Background: Chitinase 3-like 1 (CHI3L1), chitinase 3-like 2 (CHI3L2), and neuronal pentraxin II (NPTX2) are inflammatory biomarkers of Alzheimer's disease (AD). Although studies have demonstrated that cerebrospinal fluid levels of these proteins are changed in AD, no studies have undertaken a detailed examination of alterations in protein levels, cellular expression, and interaction with amyloid in the brain during the progression of AD. Methods:The study evaluated levels of both CHI3L1 and CHI3L2, NPTX2, ionized calcium-binding adapter molecule 1 (Iba1), complement component 1q (C1q), glial fibrillary acidic protein (GFAP), and CD44, in the frontal cortex of people who died with an antemortem clinical diagnosis of no cognitive impairment (NCI), mild cognitive impairment (MCI), mild/moderate AD (mAD), and severe AD (sAD) using immunoblot and immunohistochemical techniques.Results: CHI3L1-immunoreactive (-ir) astrocyte numbers were increased in the frontal cortex and white matter in sAD compared to NCI. On the other hand, increases in GFAP and Iba1-ir cell numbers were observed in MCI compared to NCI but only in white matter. Western blot analyses revealed significantly lower frontal cortex CHI3L2 levels, whereas CD44 levels were increased in sAD. No significant differences for CHI3L1, GFAP, C1q, and NPTX2 protein levels were detected between clinical groups. Strong significant correlations were found between frontal cortex CHI3L1 and Iba1-ir cell numbers in white matter and CHI3L1 and C1q protein levels in the early stages of the disease. C1q and Iba1, CD44 with CHI3L2, and GFAP protein levels were associated during disease progression. CHI3L1 and Iba1 cell numbers in white matter showed a significant associations with episodic memory and perceptual speed.Conclusions: White matter CHI3L1 inflammatory response is associated with cognitive impairment early in the onset of AD.

show abstract

“…Neuronal loss could account for the decreased abundance found in the demented brain but fails to explain the loss of synapse-associated proteins in the AsymAD brain, nor the increase in these synaptic proteins in the spinal fluid during both early and later stages of disease. One possible explanation is dysregulated endo-and exocytosis, both of which have been increasingly implicated in AD pathogenesis [71][72][73][74][75]. Indeed, aberrant synaptic glial-mediated phagocytosis of synapses, perhaps in response to aberrant intracellular Aβ production, has been proposed as a major contributor to the synaptic loss found early in disease [74].…”

Section: Discussionmentioning

confidence: 99%

Integrated Proteomics Reveals Brain-Based Cerebrospinal Fluid Biomarkers in Asymptomatic and Symptomatic Alzheimer’s Disease

Higginbotham

Ping

Dammer

et al. 2019

Preprint

View full text Add to dashboard Cite

Our results used an integrative proteomic approach to identify panels of CSF AD protein biomarkers with strong links to a variety of pathological mechanisms in the diseased brain.Abstract: Alzheimer's disease (AD) features a complex web of pathological processes beyond amyloid accumulation and tau-mediated neuronal death. To meaningfully advance AD therapeutics, there is an urgent need for novel biomarkers that comprehensively reflect these disease mechanisms. Here we applied an integrative proteomics approach to identify cerebrospinal fluid (CSF) biomarkers linked to a diverse set of pathophysiological processes in the diseased brain. Using multiplex proteomics, we identified >3,500 proteins across 40 CSF samples from control and AD patients and >12,000 proteins across 48 postmortem brain tissues from control, asymptomatic AD (AsymAD), AD, and other neurodegenerative cases. Co-expression network analysis of the brain tissues resolved 44 protein modules, nearly half of which significantly correlated with AD neuropathology. Fifteen modules robustly overlapped with proteins quantified in the CSF, including 271 CSF markers highly altered in AD. These 15 overlapping modules were collapsed into five panels of brain-linked fluid markers representing a variety of cortical functions. Neuron-enriched synaptic and metabolic panels demonstrated decreased levels in the AD brain but increased levels in diseased CSF. Conversely, glial-enriched myelination and immunity panels were highly increased in both the brain and CSF. Using high-throughput proteomic analysis, proteins from these panels were validated in an independent CSF cohort of control, AsymAD, and AD samples. Remarkably, several validated markers were significantly altered in AsymAD CSF and appeared to stratify subpopulations within this cohort. Overall, these brain-linked CSF biomarker panels represent a promising step toward a physiologically comprehensive tool that could meaningfully enhance the prognostic and therapeutic management of AD.

show abstract

Contribution of Neurons and Glial Cells to Complement-Mediated Synapse Removal during Development, Aging and in Alzheimer’s Disease

Cited by 62 publications

References 124 publications

Classical complement cascade initiating C1q protein within neurons in the aged rhesus macaque dorsolateral prefrontal cortex

Classical complement cascade initiating C1q protein within neurons in the aged rhesus macaque dorsolateral prefrontal cortex

Frontal cortex chitinase and pentraxin neuroinflammatory alterations during the progression of Alzheimer’s disease

Integrated Proteomics Reveals Brain-Based Cerebrospinal Fluid Biomarkers in Asymptomatic and Symptomatic Alzheimer’s Disease

Contact Info

Product

Resources

About