Delta-secretase cleavage of Tau mediates its pathology and propagation in Alzheimer's disease

Alzheimer's disease: Enzyme's role in disease progression The identification of an enzyme that plays a critical role in the progression of Alzheimer's disease (AD) could lead to novel therapeutic interventions. In the earliest stage of AD, the build-up of Tau protein aggregates causes degeneration of a site in the brainstem. These abnormal Tau accumulations then spread to other parts of the brain. Recent research suggests that an enzyme called delta-secretase cleaves Tau and other key molecules, making Tau more prone to forming aggregates and thus facilitating disease progression. Keqiang Ye and co-workers at Emory University School of Medicine in Atlanta, USA, reviewed current understanding of the role of delta-secretase in AD pathology. Studies show that delta-secretase expression levels are high in aged mice and AD brains. Inhibiting delta-secretase could therefore limit neurodegeneration and alleviate cognitive deficits in patients. Alzheimer's disease (AD) is a progressive neurodegenerative disease with age as a major risk factor. AD is the most common dementia with abnormal structures, including extracellular senile plaques and intraneuronal neurofibrillary tangles, as key neuropathologic hallmarks. The early feature of AD pathology is degeneration of the locus coeruleus (LC), which is the main source of norepinephrine (NE) supplying various cortical and subcortical areas that are affected in AD. The spread of Tau deposits is first initiated in the LC and is transported in a stepwise manner from the entorhinal cortex to the hippocampus and then to associative regions of the neocortex as the disease progresses. Most recently, we reported that the NE metabolite DOPEGAL activates delta-secretase (AEP, asparagine endopeptidase) and triggers pathological Tau aggregation in the LC, providing molecular insight into why LC neurons are selectively vulnerable to developing early Tau pathology and degenerating later in the disease and how delta-secretase mediates the spread of Tau pathology to the rest of the brain. This review summarizes our current understanding of the crucial role of delta-secretase in driving and spreading AD pathologies by cleaving multiple critical players, including APP and Tau, supporting that blockade of delta-secretase may provide an innovative disease-modifying therapeutic strategy for treating AD.