It is well established that chronic inflammation in brain tissue contributes to the onset and progression of neurodegenerative conditions such as Alzheimer’s disease. Short-term inflammation is a necessary part of the response to injury and infection, required to mobilize immune cells. Inflammation that fails to resolve and continues unabated for the long term is disruptive to tissue function, however, and very definitely harmful. Unfortunately, aging is characterized by progressively increasing chronic inflammation, the result of processes such as accumulation of senescent cells and harmful metabolic byproducts.
Alzheimer’s is a complicated condition. It is thought to begin with a slow aggregation of amyloid-β deposits over the course of years. This produces mild cognitive impairment and a state of chronic inflammation sufficient to trigger a later, much more harmful aggregation of altered tau protein. This later stage leads to dementia and death. Clearing amyloid-β from the brain hasn’t produced meaningful benefits to patients, however, suggesting that it is not the key process in the development of the condition.
An alternative view of Alzheimer’s disease is that persistent infection causes both chronic inflammation and amyloid-β aggregation, as amyloid-β is actually a part of the innate immune system – an anti-microbial peptide. In this view the more important problem is the chronic inflammation of aging, the constant over-activation of the immune system in brain tissue. The best targets for treatment are thus the set of mechanisms that produce that inflammation, such as senescent cell accumulation, the presence of persistent pathogens such as herpesviruses, and so forth. Supporting evidence is emerging for this position, such as today’s research materials, in which the immune response is linked to amyloid-β production.
Recent studies have found that beta-amyloid has antiviral and antimicrobial properties, suggesting a possible link between the immune response against infections and the development of Alzheimer’s disease. Researchers have now discovered clear evidence of this link: A protein called IFITM3 that is involved in the immune response to pathogens also plays a key role in the accumulation of beta-amyloid in plaques. IFITM3 alters the activity of an enzyme called gamma-secretase, which chops up precursor proteins into the fragments of beta-amyloid that make up plaques. Researchers found that removing IFITM3 decreased the activity of the gamma-secretase enzyme and, as a result, reduced that number of amyloid plaques that formed in a mouse model of the disease.
Neuroinflammation (inflammation in the brain) has emerged as an important line of inquiry in Alzheimer’s disease research. Markers of inflammation, such as certain immune molecules called cytokines, are boosted in Alzheimer’s disease mouse models and in the brains of people with Alzheimer’s disease. This study is the first to provide a direct link between this inflammation and plaque development – by way of IFITM3.
Scientists know that the production of IFITM3 starts in response to activation of the immune system by invading viruses and bacteria. These observations, combined with the new findings that IFITM3 directly contributes to plaque formation, suggest that viral and bacterial infections could increase the risk of Alzheimer’s disease development. Indeed, researchers found that the level of IFITM3 in human brain samples correlated with levels of certain viral infections as well as with gamma-secretase activity and beta-amyloid production. Age is the number one risk factor for Alzheimer’s, and the levels of both inflammatory markers and IFITM3 increased with advancing age in mice, the researchers found.
Innate immunity is associated with Alzheimer’s disease1, but the influence of immune activation on the production of amyloid-β is unknown. Here we identify interferon-induced transmembrane protein 3 (IFITM3) as a γ-secretase modulatory protein, and establish a mechanism by which inflammation affects the generation of amyloid-β.
Inflammatory cytokines induce the expression of IFITM3 in neurons and astrocytes, which binds to γ-secretase and upregulates its activity, thereby increasing the production of amyloid-β. The expression of IFITM3 is increased with ageing and in mouse models that express familial Alzheimer’s disease genes. Furthermore, knockout of IFITM3 reduces γ-secretase activity and the formation of amyloid plaques in a transgenic mouse model (5xFAD) of early amyloid deposition. IFITM3 protein is upregulated in tissue samples from a subset of patients with late-onset Alzheimer’s disease that exhibit higher γ-secretase activity. The amount of IFITM3 in the γ-secretase complex has a strong and positive correlation with γ-secretase activity in samples from patients with late-onset Alzheimer’s disease. These findings reveal a mechanism in which γ-secretase is modulated by neuroinflammation via IFITM3 and the risk of Alzheimer’s disease is thereby increased.