Exacerbated mitochondrial dynamic abnormalities without evident tau pathology in rapidly progressive Alzheimer's disease

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BACKGROUND: Rapidly progressive Alzheimer's disease (rpAD) is a clinical subtype distinguished by its rapid cognitive decline and shorter disease duration. rpAD, like typical AD (tAD), is characterized by underlying neuropathology of amyloid plaques and neurofibrillary tangles. There is early evidence that the composition of amyloid plaques could vary between the rpAD and tAD. Differences in tau pathology between rpAD and tAD are also of interest. Additionally, mitochondrial dysfunction is a key early-stage change in tAD but has not yet been evaluated in rpAD. OBJECTIVE: To deepen our understanding of the underlying pathophysiological processes specific to rpAD, we explore potential changes in tau pathology and mitochondrial dysfunction in rpAD compared to tAD. METHODS: We performed immunohistochemical and immunoblot analyses of tau, phosphorylated tau, and key regulators of mitochondrial dynamics and bioenergetics in postmortem human temporal cortex tissues obtained from patients diagnosed with tAD or rpAD, and tissues from age-matched normal subjects. RESULTS: tAD was characterized by significant tau phosphorylation at the PHF1 epitope. Unexpectedly, rpAD showed milder PHF1 tau phosphorylation, similar to that of age-matched controls. Despite these differences in tau pathology, both tAD and rpAD exhibited a significant decrease in the key regulators of mitochondrial dynamics and bioenergetics compared to controls. However, the decline in mitochondrial dynamics regulators was more pronounced in rpAD. CONCLUSIONS: These findings suggest divergent pathological processes between tAD and rpAD, specifically in terms of tau pathology and mitochondrial dynamic abnormalities, which underscore the necessity for different approaches to understand and potentially treat various AD subtypes.

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