The role of ADAM10 in astrocytes: Implications for Alzheimer’s disease

Abstract

Much of the early research into AD relies on a neuron-centric view of the brain, however, evidence of multiple altered cellular interactions between glial cells and the vasculature early in AD has been demonstrated. As such, alterations in astrocyte function are widely recognized a contributing factor in the pathogenesis of AD. The processes by which astrocytes may be involved in AD make them an interesting target for therapeutic intervention, but in order for this to be most effective, there is a need for the specific mechanisms involving astrocyte dysfunction to be investigated. “α disintegrin and metalloproteinase” 10 (ADAM10) is capable of proteolytic cleavage of the amyloid precursor protein which prevents amyloid-β generation. As such ADAM10 has been identified as an interesting enzyme in AD pathology. ADAM10 is also known to play a role in a significant number of cellular processes, most notable in notch signaling and in inflammatory processes. There is a growing research base for the involvement of ADAM10 in regulating astrocytic function, primarily from an immune perspective. This review aims to bring together available evidence for ADAM10 activity in astrocytes, and how this relates to AD pathology.

Systematic druggable genome-wide Mendelian randomisation identifies therapeutic targets for Alzheimer’s disease

“… 52 Moreover, ADAM10 is an important enzyme in AD pathology and may function in AD via astrocytes. 53 2,4-Diacetylphloroglucinol reduces Aβ production and secretion by regulating ADAM10 and its intracellular trafficking in cellular and animal models of AD. 54 Furthermore, the development of ADAM10 endocytosis inhibitors for AD treatment yielded promising preclinical results.…”

Altered metabolic function induced by amyloid-beta oligomers and PSEN1-mutations in iPSC-derived astrocytes

“…We add further evidence of a reduction in non-amyloidogenic AβPP processing via lower ADAM10 activity and reduced sAβPPα secretion was detected in PSEN1 astrocytes compared to controls. The relationship between the presence of the PSEN1 mutation and reduced ADAM10 activity in astrocytes is not known, and remains an interesting topic for further investigation, 70 .…”

ADAM10 Gene Variants in AD Patients and Their Relationship to CSF Protein Levels

“…Moreover, a non-transgenic mouse model that mimics the early stages of AD was obtained by blocking ADAM10 activity (together with its synapse-associated protein partner), which shifted APP metabolism towards amyloidogenesis [ 10 ]. In addition to APP proteolysis, ADAM10 is known to cleave a number of other proteins, and also plays a role in synaptic functions, in the regulation of dendritic spine formation and stabilization, and in regulating the astrocytic immune response [ 11 , 12 ].…”

“…However, a more recent study supports that ADAM10 levels are increased in plasma and CSF of cases with mild AD, though in these samples the protease was shown to be inactive [ 19 ]. As ADAM10 is active as a membrane-anchored protease, it is possible that soluble ADAM10 that has undergone ectodomain shedding represents a soluble inactive protein, and increased levels could be linked to reduced overall enzyme activity [ 11 , 19 , 20 ]…”