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

Datta, Dibyadeep; Leslie, Shannon; Morozov, Yury M.; Duque, Alvaro; Rakić, Paško; Dyck, Christopher H. van; Nairn, Angus C.; Arnsten, Amy F.T.

doi:10.1186/s12974-019-1683-1

Cited by 42 publications

(35 citation statements)

References 71 publications

(126 reference statements)

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“…Aged mice with C1q deficiency exhibit significantly less cognitive and memory decline compared with wild-type mice (170). Marked increases in C1q levels are found in dendritic spines at synapses in the aged rhesus macaque dorsolateral prefrontal cortex as well as glia ensheathed synapses, suggesting C1q-tagged synapse elimination by glial phagocytosis as a possible mechanism for age-related degeneration (171). C57BL/6J (B6) mice (at 16 months of age) show agedependent neuron loss in hippocampal CA3 but not in CA1, which is not observed complement C3-deficient B6 mice.…”

Section: Complement In Aging Brainmentioning

confidence: 93%

TLR4 Cross-Talk With NLRP3 Inflammasome and Complement Signaling Pathways in Alzheimer's Disease

2020

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Amyloid plaques, mainly composed of abnormally aggregated amyloid β-protein (Aβ) in the brain parenchyma, and neurofibrillary tangles (NFTs), consisting of hyperphosphorylated tau protein aggregates in neurons, are two pathological hallmarks of Alzheimer's disease (AD). Aβ fibrils and tau aggregates in the brain are closely associated with neuroinflammation and synapse loss, characterized by activated microglia and dystrophic neurites. Genome-wide genetic association studies revealed important roles of innate immune cells in the pathogenesis of late-onset AD by recognizing a dozen genetic risk loci that modulate innate immune activities. Furthermore, microglia, brain resident innate immune cells, have been increasingly recognized to play key, opposing roles in AD pathogenesis by either eliminating toxic Aβ aggregates and enhancing neuronal plasticity or producing proinflammatory cytokines, reactive oxygen species, and synaptotoxicity. Aggregated Aβ binds to toll-like receptor 4 (TLR4) and activates microglia, resulting in increased phagocytosis and cytokine production. Complement components are associated with amyloid plaques and NFTs. Aggregated Aβ can activate complement, leading to synapse pruning and loss by microglial phagocytosis. Systemic inflammation can activate microglial TLR4, NLRP3 inflammasome, and complement in the brain, leading to neuroinflammation, Aβ accumulation, synapse loss and neurodegeneration. The host immune response has been shown to function through complex crosstalk between the TLR, complement and inflammasome signaling pathways. Accordingly, targeting the molecular mechanisms underlying the TLR-complement-NLRP3 inflammasome signaling pathways can be a preventive and therapeutic approach for AD.

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Section: Complement In Aging Brainmentioning

confidence: 93%

TLR4 Cross-Talk With NLRP3 Inflammasome and Complement Signaling Pathways in Alzheimer's Disease

2020

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“…Furthermore, understanding the drivers of agerelated loss of PDE4D is critical. Previous work with the extreme aged cohort utilized in this study, revealed an agerelated increase in complement signaling protein C1qA (Datta et al, 2020). Investigating the ways in which age-related signaling changes may contribute to loss of PDE4D may demonstrate new therapeutic avenues to alleviate age-related cognitive decline and potentially AD risk.…”

Section: Pde4d In Aging and Admentioning

confidence: 66%

“…The extreme aged animals came from a variety of cohorts where only a few animals (N = 3) survived to the target age of 30 months; however, we collected a full cohort (N = 10) with an average age of 27.8 months. Tissue from this extreme aged cohort was also analyzed in Datta et al, 2020. These fragile animals were not cognitively tested.…”

Section: Subjectsmentioning

confidence: 99%

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Phosphodiesterase PDE4D Is Decreased in Frontal Cortex of Aged Rats and Positively Correlated With Working Memory Performance and Inversely Correlated With PKA Phosphorylation of Tau

Leslie

Datta

Christensen

et al. 2020

Front. Aging Neurosci.

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Age is the largest risk factor for Alzheimer's disease (AD) and contributes to cognitive impairment in otherwise healthy individuals. Thus, it is critical that we better understand the risk aging presents to vulnerable regions of the brain and carefully design therapeutics to address those effects. In this study we examined age-related changes in cAMP-regulatory protein, phosphodiesterase 4D (PDE4D). Inhibition of PDE4D is currently under investigation as a therapeutic target for AD based on memoryenhancing effects in rodent hippocampus. Therefore, it is important to understand the role of PDE4D in brain regions particularly vulnerable to disease such as the frontal association cortex (FC), where cAMP signaling can impair working memory via opening of potassium channels. We found that PDE4D protein level was decreased in the FC of both moderately and extremely aged rats, and that PDE4D level was correlated with performance on a FC-dependent working memory task. In extremely aged rats, PDE4D was also inversely correlated with levels of phosphorylated tau at serine 214 (S214), a site phosphorylated by protein kinase A. In vitro studies of the PDE4D inhibitor, GEBR-7b, further illustrated that inhibition of PDE4D activity enhanced phosphorylation of tau. pS214-tau phosphorylation is associated with early AD tau pathology, promotes tau dissociation from microtubules and primes subsequent tau hyperphosphorylation at other critical AD-related sites. Age-related loss of PDE4D may thus contribute to the specific vulnerability of the FC to degeneration in AD, and play a critical role in normal cAMP regulation, cautioning against the use of pan-PDE4D inhibitors as therapeutics.

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“…Excessive cytosolic calcium also induces calcium overload of mitochondria that can initiate inflammatory signaling, and under extreme conditions, apoptosis [129][130][131]. The data suggest that sustained, moderate levels of calcium dysregulation contribute to mitochondrial abnormalities [164,165] and inflammation [166] with advancing age in the primate dlPFC. Complement C1q is expressed in aged monkey dlPFC near dysmorphic mitochondria and near synapses on spines [166], which is a likely forerunner to age-related loss of spines [167].…”

Section: Relevance To Age-related Cognitive Disordersmentioning

confidence: 88%

The genie in the bottle-magnified calcium signaling in dorsolateral prefrontal cortex

2020

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Neurons in the association cortices are particularly vulnerable in cognitive disorders such as schizophrenia and Alzheimer’s disease, while those in primary visual cortex remain relatively resilient. This review proposes that the special molecular mechanisms needed for higher cognitive operations confer vulnerability to dysfunction, atrophy, and neurodegeneration when regulation is lost due to genetic and/or environmental insults. Accumulating data suggest that higher cortical circuits rely on magnified levels of calcium (from NMDAR, calcium channels, and/or internal release from the smooth endoplasmic reticulum) near the postsynaptic density to promote the persistent firing needed to maintain, manipulate, and store information without “bottom-up” sensory stimulation. For example, dendritic spines in the primate dorsolateral prefrontal cortex (dlPFC) express the molecular machinery for feedforward, cAMP–PKA–calcium signaling. PKA can drive internal calcium release and promote calcium flow through NMDAR and calcium channels, while in turn, calcium activates adenylyl cyclases to produce more cAMP–PKA signaling. Excessive levels of cAMP–calcium signaling can have a number of detrimental effects: for example, opening nearby K+ channels to weaken synaptic efficacy and reduce neuronal firing, and over a longer timeframe, driving calcium overload of mitochondria to induce inflammation and dendritic atrophy. Thus, calcium–cAMP signaling must be tightly regulated, e.g., by agents that catabolize cAMP or inhibit its production (PDE4, mGluR3), and by proteins that bind calcium in the cytosol (calbindin). Many genetic or inflammatory insults early in life weaken the regulation of calcium–cAMP signaling and are associated with increased risk of schizophrenia (e.g., GRM3). Age-related loss of regulatory proteins which result in elevated calcium–cAMP signaling over a long lifespan can additionally drive tau phosphorylation, amyloid pathology, and neurodegeneration, especially when protective calcium binding proteins are lost from the cytosol. Thus, the “genie” we need for our remarkable cognitive abilities may make us vulnerable to cognitive disorders when we lose essential regulation.

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

Cited by 42 publications

References 71 publications

TLR4 Cross-Talk With NLRP3 Inflammasome and Complement Signaling Pathways in Alzheimer's Disease

TLR4 Cross-Talk With NLRP3 Inflammasome and Complement Signaling Pathways in Alzheimer's Disease

Phosphodiesterase PDE4D Is Decreased in Frontal Cortex of Aged Rats and Positively Correlated With Working Memory Performance and Inversely Correlated With PKA Phosphorylation of Tau

The genie in the bottle-magnified calcium signaling in dorsolateral prefrontal cortex

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