Role of Metalloproteinases in Diabetes-associated Mild Cognitive Impairment

Abstract

Diabetes has been linked to an increased risk of mild cognitive impairment (MCI), a condition characterized by a subtle cognitive decline that may precede the development of dementia. The underlying mechanisms connecting diabetes and MCI involve complex interactions between metabolic dysregulation, inflammation, and neurodegeneration. A critical mechanism implicated in diabetes and MCI is the activation of inflammatory pathways. Chronic low-grade inflammation, as observed in diabetes, can lead to the production of pro-inflammatory cytokines such as tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), interleukin-1 beta (IL-1β), and interferon-gamma (IFNγ), each of which can exacerbate neuroinflammation and contribute to cognitive decline. A crucial enzyme involved in regulating inflammation is ADAM17, a disintegrin, and metalloproteinase, which can cleave and release TNF-α from its membrane-bound precursor and cause it to become activated. These processes, in turn, activate additional inflammation-related pathways, such as AKT, NF-κB, NLP3, MAPK, and JAK-STAT pathways. Recent research has provided novel insights into the role of ADAM17 in diabetes and neurodegenerative diseases. ADAM17 is upregulated in both diabetes and Alzheimer's disease, suggesting a shared mechanism and implicating inflammation as a possible contributor to much broader forms of pathology and pointing to a possible link between inflammation and the emergence of MCI. This review provides an overview of the different roles of ADAM17 in diabetes-associated mild cognitive impairment diseases. It identifies mechanistic connections through which ADAM17 and associated pathways may influence the emergence of mild cognitive impairment.

Keywords: MMPs; Mild cognitive impairment; T2DM; dementia; diabetes; inflammation..

Fig. (1)

Involvement of ADAM17 in brain physiology (A, B) and neurodegenerative disease (C). (A) ADAM17 cleaves a series of proteins related to neural development (L1 and NCAM), learning and memory (LTD and NRP), and plasticity (RA175/SynCAM1) is regulated by iRhom1. (B) In neurons, iRhom1 may have a beneficial function as ADAM17 is responsible for processing APP into a non-amyloid form, known as sAAPα. (C) In microglia cells, protein processing can lead to impairment of APP processing (consequent to cleavage by TREM2), microglia activation (due to the release of pro-inflammatory cytokines, such as TNF-α and IL-6R and leukocyte), and upregulated inflammatory response (due to the cleave of adhesion molecules such as VCAM-1, ICAM-1 and CXCL1) causing damage to the blood-brain barrier damage.

Fig. (2)

Crosstalk mechanisms related to diabetes, cognitive impairment, and ADAM17. The trilogy of diabetes consisted of increased concentration of free-fat-acids (FFA), development of chronic inflammation, and consequent insulin resistance, which leads to hyperglycemia. Hyperglycemia causes dysregulation of cell signaling pathways related to insulin resistance (PI3K/AKT), inflammation (NF-kB, MAPK, and JAK-STAT), and oxidative stress (NLPR3), which eventually will lead to the activation of glial cells and subsequent neurodegeneration. The primary substrates cleaved by ADAM17 include cytokines TNF-α and IL-6R, which cause increased activation of NF-kB, NLPR3, MAPK, and JAK-STAT and damage the blood-brain barrier and neuroinflammation. The increased shedding of TNF-α, and TREM2 by ADAM17 will accentuate the inhibition of the PI3K/AKT pathway, leading to greater impairment in brain insulin resistance.