Dementia is a chronic condition characterized by a progressive cognitive impairment that leads to functional disability. Recent research has shown the implication of neuroinflammation in Alzheimer’s Disease pathogenesis (Ref 1). In this article you will find some interesting facts about the involvement of neuroinflammation in the pathogenesis and development of Alzheimer’s Disease.
Key numbers about Dementia and Alzheimer’s Disease
- Almost 47 million people suffer from dementia worldwide. This number is expected to increase, reaching 131.5 million by 2050.
- 1 every 3 seconds is the number of new cases around the world.
- The main form of Dementia is Alzheimer’s Disease (AD), since 60% to 80% of all dementia cases are diagnosed as AD (Ref 2).
- 1907 was the year when Alzheimer’s Disease was first described by Alois Alzheimer as the principal cause of dementia in the elderly.
- 3 molecular pillars seem to drive AD pathogenesis. For decades, extracellular deposition of beta amyloid peptides and intraneuronal formation of neurofibrils were considered as the two major pathological hallmarks of AD pathogenesis. However, the latest research shows that induction of inflammatory signaling pathways leads to the production and release of immune mediators, which ultimately compromises neuronal function and causes cell death and thus contributes to the severity of AD.
Key inflammatory cells involved in neuroinflammation
Brain injuries, nerve tissue lesions, and local neurodegenerative areas show activation of glial cells, essentially the reaction of resident microglia and astrocytes. Microglial cells are considered the macrophages of the central nervous system (CNS), and are only found in the brain where they represent 10 to 15% of its cells. In Alzheimer’s Disease, glial cells and inflammatory responses are associated with amyloid plaque deposition, initially identified as a disease biomarker. Plaques that are surrounded by microglia and astrocytes produce cytokines, chemokines, and other factors that are involved in inflammatory processes. The overactivation and recruitment of microglia in Alzheimer’s Disease is due to the accumulation of amyloid-β proteins, which further activate microglia and so provoke neuronal damage (Fig. 2). Activated microglia migrate to the site of plaque formation and penetrate the plaques, which leads to the production of pro-inflammatory cytotoxic molecules such as NO and TNF-α. In parallel, the sustained activation of the brain’s resident microglia and other immune cells has been demonstrated to exacerbate both amyloid and tau pathologies, and may serve as a link in the pathogenesis of the disease.
Identification of potential key players
The activation of glial cells leads to the production of several proteins involved in AD pathogenesis and the latest research on neuroinflammation has highlighted new potential players. Here is a non-exhaustive list:
TREM2 (Ref 3): this protein is also known as Triggering Receptor Expressed on Myeloid Cells 2. The TREM family of receptors regulates the activity of various cell types in the immune system, including microglia (Fig. 3). TREM-2 requires the adaptor protein DAP12 for downstream signaling. Rare loss-of-function variants in the gene encoding TREM2 increase the risk of AD development in humans (Ref 4). Microglia respond to Aβ accumulation and neurodegenerative lesions by evolving into disease-associated microglia (DAM). DAM attenuate the progression of neurodegeneration in certain mouse models, but inappropriate DAM activation accelerates neurodegenerative disease in other models. TREM2 is essential to maintain microglial metabolic fitness during stress events, enabling microglial progression to a fully mature DAM profile and ultimately sustaining the microglial response to Aβ plaque-induced pathology.
CD33 (Ref 5): this protein participates in the regulation of phagocytosis in microglial cells. Some studies have shown the correlation of a mutation in the CD33 gene with sensitivity to Alzheimer’s Disease.
TNF-α (Ref 1): this protein is one of the most important proinflammatory cytokines involved in AD. TNF-α binds to two main receptors, TNFR1 and TNFR2. The overexpression of TNFR1 in mouse hippocampal tissue is necessary for the activation of NFκB- and Aβ-induced neuronal apoptosis. Increased levels of TNF-α have been reported in both the brains and plasma of patients with AD. Aβ can directly stimulate microglial production of TNF-α through activation of the transcription factor NFκB
(images-LR-alzheimers-disease-trem2-simpified-pathway)
Example of TREM2 simplified pathway
Identified factors facilitating neuroinflammation
Aβ deposition alone could be enough to induce an inflammatory response which contributes to AD development. Thus, environmental AD risk factors may affect disease onset through a sustained neuroinflammatory drive (Fig. 4).
First, ageing is the major risk factor for the development of AD. Ageing is correlated with a low grade chronic up-regulation of the systemic pro-inflammatory response and a relative loss of adaptive immunity and of the T helper 2 response, a phenomenon known as inflammaging (Ref 6). The causes for inflammaging are mainly due to factors that increase the imbalance between inflammatory and anti-inflammatory factors as we age. The combination of these two factors, microglial priming and inflammaging, results in an increased vulnerability to acute and/or chronic systemic inflammatory events as we age, and in the development of AD.
Secondly, obesity can be an aggravating factor that contributes to AD development. Obesity increases the propensity to acquire more bacterial or viral infections, and directly increases the probability of systemic inflammation (Ref 1). In AD, obesity has been identified as a risk factor mostly due to a subset of related risks, such as a high cholesterol diet and a sedentary life style. As a probable consequence of obesity, Type II diabetes has been demonstrated to accelerate memory dysfunction and neuroinflammation in an AD mouse model. Obesity can also lead to reduced gut microbial diversity, which has been associated with increased levels of proinflammatory markers in the peripheral blood and thus could be a factor contributing to AD risk.
Several studies have also established traumatic brain injury (TBI) as a risk factor for the development of AD. Experimentally, TBI aggravates learning and memory deficits as well as the deposition of Aβ in murine AD models. Experimental and human studies have shown that microglial activation can persist for months and even years after TBI.
Chronic neuroinflammation has adverse effects on brain homeostasis and contributes to the breakdown of the blood-brain barrier, which heightens the migration of peripheral immune cells into the central nervous system and, possibly, increases the likelihood of developing AD. Over the years, thanks to constantly-advancing research on the topic, neuroinflammation has clearly become a new therapeutic avenue for potential drug discovery in the combat against Alzheimer’s Disease.
Revvity Inc. does not endorse or make recommendations with respect to research, medication, or treatments. All information presented is for informational purposes only and is not intended as medical advice. For country specific recommendations, please consult your local health care professionals.
Ref 1: Neuroinflammation in Alzheimer's disease - PubMed (nih.gov)
Ref 2 : Neurobiology of Alzheimer’s Disease - ScienceDirect
Ref 3 : New insights into the role of TREM2 in Alzheimer's disease - PubMed (nih.gov)
Ref 4 : TREM2 - a key player in microglial biology and Alzheimer disease - PubMed (nih.gov)
Ref 5: Repression of phagocytosis by human CD33 is not conserved with mouse CD33 - PubMed (nih.gov)
Ref 6: Review: systemic inflammation and Alzheimer's disease - PubMed (nih.gov)
