The Distinct Role of ADAM17 in APP Proteolysis and Microglial Activation Related to Alzheimer’s Disease

Abstract

Alzheimer's disease (AD) is a progressive neurodegenerative disease with the symptom of cognitive impairment. The deposition of amyloid β (Aβ) peptide is believed to be the primary cause to neuronal dystrophy and eventually dementia. Aβ is the proteolytic product from its precursor amyloid precursor protein (APP) by β- and γ- secretase. An optional cleavage by α-secretase happens inside the Aβ domain. ADAM17 is supposed to be the regulated α-secretase of APP. Enhanced activity of ADAM17 leads to the increasing secretion of neuroprotective soluble APP α fragment and reduction of Aβ generation, which may be benefit to the disease. ADAM17 is then considered the potential therapeutic target for AD. Microglia activation and neuroinflammation is another important event in AD pathogenesis. Interestingly, ADAM17 also participates in the cleavage of many other membrane-bound proteins, especially some inflammatory factors related to microglia activation. The facilitating role of ADAM17 in inflammation and further neuronal damage has also been illustrated. In results, the activation of ADAM17 as the solution to AD may be a tricky task. The comprehensive consideration and evaluation has to be carried out carefully before the final treatment. In the present review, the distinct role of ADAM17 in AD-related APP shedding and neuroinflammatory microglial activation will be carefully discussed.

Early candidate urine biomarkers for detecting Alzheimer’s disease before beta amyloid plaque deposition in an APP (swe)/PSEN1dE9transgenic mouse model

“…A larger number of differential urine proteins were identified in 8-month-old mice and indicated other AD-related biological processes. Proteolysis processes were overrepresented and reported to be associated with APP proteolysis, which is consistent with the pathology of AD [72]. In addition, the urinary proteins that were related to fibrinolysis may be factors contributing to AD [73].…”

The Role of Neuronal Pentraxin 2 (NP2) in Regulating Glutamatergic Signaling and Neuropathology

“…Interestingly, NPR is upregulated in soluble cortical homogenate fractions of 3-9-month-old APP/PS1 rats, but not at 18-20 months (Bilousova et al, 2015). The suggestion is that the lack of soluble NPR in the late-stage animals was due to a degradation in TACE activity (Qian et al, 2016) leading to less cleaved NPR in the soluble preparations. The increase in glutamate release that is evident before plaque deposition in AD mouse models (Cummings et al, 2015) may be due, at least in part, to the upregulation of NP1 and NPR (Cummings et al, 2017).…”

The interplay between aging‐associated loss of protein homeostasis and extracellular vesicles in neurodegeneration

“…In opposition to BACE1, APP can be cleaved also by the non-amyloidogenic alpha-secretase activity (believed to be carried out by ADAM10 or ADAM17), which releases an APP-αCTF fragment that does not generate Aβ after γ-secretase cleavage (Jorissen et al, 2010;Kuhn et al, 2010;Qian, Shen, & Wang, 2016).…”