Inflammatory mechanisms in neurodegeneration and Alzheimer's disease: The role of the complement system

Abstract The complement system is part of the innate immune system that comprises several small proteins activated by sequential cleavages. The majority of these complement components, such as components 3a (C3a) and C5a, are chemotactic and pro-inflammatory. However, in this study, we revealed an inhibitory role of complement component 8 gamma (C8G) in neuroinflammation. In patients with Alzheimer's disease, who exhibit strong neuroinflammation, we found higher C8G levels in brain tissue, CSF, and plasma. Our novel findings also showed that the expression level of C8G increases in the inflamed mouse brain, and that C8G is mainly localized to brain astrocytes. Experiments using recombinant C8G protein and shRNA-mediated knockdown showed that C8G inhibits glial hyperactivation, neuroinflammation, and cognitive decline in acute and chronic animal models of Alzheimer’s disease. Additionally, we identified sphingosine-1-phosphate receptor 2 (S1PR2) as a novel interaction protein of C8G and demonstrated that astrocyte-derived C8G interacts with S1PR2 to antagonize the pro-inflammatory action of S1P in microglia. Taken together, our results reveal the previously unrecognized role of C8G as a neuroinflammation inhibitor. Our findings pave the way towards therapeutic containment of neuroinflammation in Alzheimer’s disease and related neurological diseases.

Download Full-text

Complement System in Alzheimer’s Disease

International Journal of Molecular Sciences ◽

10.3390/ijms222413647 ◽

2021 ◽

Vol 22 (24) ◽

pp. 13647

Author(s):

Akash Shah ◽

Uday Kishore ◽

Abhishek Shastri

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Complement System ◽

Short Term Memory ◽

Neurodegenerative Disorder ◽

Membrane Attack Complex ◽

Future Research ◽

Chronic Neuroinflammation ◽

The Central Nervous System ◽

The Complement System

Alzheimer’s disease is a type of dementia characterized by problems with short-term memory, cognition, and difficulties with activities of daily living. It is a progressive, neurodegenerative disorder. The complement system is an ancient part of the innate immune system and comprises of more than thirty serum and membrane-bound proteins. This system has three different activating pathways and culminates into the formation of a membrane attack complex that ultimately causes target cell lysis (usually pathogens) The complement system is involved in several important functions in the central nervous system (CNS) that include neurogenesis, synaptic pruning, apoptosis, and neuronal plasticity. Here, we discuss how the complement system is involved in the effective functioning of CNS, while also contributing to chronic neuroinflammation leading to neurodegenerative disorders such as Alzheimer’s disease. We also discuss potential targets in the complement system for stopping its harmful effects via neuroinflammation and provide perspective for the direction of future research in this field.

Download Full-text

The role of abnormal mitochondrial dynamics in the pathogenesis of Alzheimer's disease

Yearbook of Neurology and Neurosurgery ◽

10.1016/s0513-5117(09)79132-x ◽

2009 ◽

Vol 2009 ◽

pp. 149-150

Author(s):

J.P. Blass

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Mitochondrial Dynamics

Download Full-text

Dissecting the role of Corticotropin-releasing hormone receptor type 1 in Alzheimer's Disease

Pharmacopsychiatry ◽

10.1055/s-0031-1292513 ◽

2011 ◽

Vol 44 (06) ◽

Author(s):

K Lerche ◽

M Willem ◽

K Kleinknecht ◽

C Romberg ◽

U Konietzko ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Hormone Receptor ◽

Receptor Type ◽

Corticotropin Releasing Hormone ◽

Releasing Hormone

Download Full-text

Role of melatonin in regulating neurogenesis: Implications for the neurodegenerative pathology and analogous therapeutics for Alzheimer’s disease

Melatonin Research ◽

10.32794/mr11250059 ◽

2020 ◽

Vol 3 (2) ◽

pp. 216-242 ◽

Cited By ~ 1

Author(s):

Mayuri Shukla ◽

Areechun Sotthibundhu ◽

Piyarat Govitrapong

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Adult Neurogenesis ◽

Adult Brain ◽

Therapeutic Approaches ◽

Therapeutic Implications ◽

Cell Proliferation And Differentiation ◽

Proliferation And Differentiation ◽

Progenitor Cell Proliferation

The revelation of adult brain exhibiting neurogenesis has established that the brain possesses great plasticity and that neurons could be spawned in the neurogenic zones where hippocampal adult neurogenesis attributes to learning and memory processes. With strong implications in brain functional homeostasis, aging and cognition, various aspects of adult neurogenesis reveal exuberant mechanistic associations thereby further aiding in facilitating the therapeutic approaches regarding the development of neurodegenerative processes in Alzheimer’s Disease (AD). Impaired neurogenesis has been significantly evident in AD with compromised hippocampal function and cognitive deficits. Melatonin the pineal indolamine augments neurogenesis and has been linked to AD development as its levels are compromised with disease progression. Here, in this review, we discuss and appraise the mechanisms via which melatonin regulates neurogenesis in pathophysiological conditions which would unravel the molecular basis in such conditions and its role in endogenous brain repair. Also, its components as key regulators of neural stem and progenitor cell proliferation and differentiation in the embryonic and adult brain would aid in accentuating the therapeutic implications of this indoleamine in line of prevention and treatment of AD.

Download Full-text