Abstract
Age is the most significant risk factor for Alzheimer’s disease (AD), and understanding its role in specific aspects of AD pathology will be critical for therapeutic development. Neurofibrillary tangles composed of hyperphosphorylated tau are a quintessential hallmark of AD. To study age-related changes in tau phosphorylation, we developed a simple, antibody-free approach for single shot analysis of tau phosphorylation across the entire protein by liquid-chromatography tandem mass spectrometry. This methodology is species independent; thus, while initially developed in a rodent model, we utilized this technique to analyze 36 phosphorylation sites on rhesus monkey tau from the prefrontal cortex (PFC), a region vulnerable to AD-linked degeneration. Data are available via ProteomeXchange with identifier PXD027971. We identified novel, age-related changes in tau phosphorylation in the rhesus monkey PFC and analyzed patterns of phosphorylation change across domains of the protein. We confirmed a significant increase and positive correlation with age of phosphorylated serine 235 tau and phosphorylated serine 396 tau levels in an expanded cohort of 14 monkeys. Histology showed robust labeling for tau phosphorylated at these sites in vulnerable layer III pyramidal cells in the PFC. The results presented in this study suggest an important role of the natural aging process in tau phosphorylation in rhesus monkey.
Highlights
Alzheimer’s disease (AD) represents a major public health crisis worldwide
To study age-related changes in tau phosphorylation that may correlate with AD tau pathology risk, we studied monkey dorsolateral prefrontal cortex from both young and aged animals
The ability to quickly analyze a broad spectrum of tau phosphorylation appears useful to better understanding the risk that aging plays in AD etiology
Summary
Alzheimer’s disease (AD) represents a major public health crisis worldwide. The vast majority of AD cases are sporadic. The primary constituent of NFTs, tau, is a microtubule-associated protein that binds and stabilizes microtubules (Murphy et al, 1977; Kutter et al, 2016; Barbier et al, 2019). Phosphorylation of tau plays an important role in modulating the protein’s normal physiology; notably, decreasing tau’s binding and stabilizing of microtubules (Mandelkow et al, 1995; Barbier et al, 2019). Recent research suggests the pattern of tau phosphorylation, rather than levels at individual phosphorylation sites, may play a critical role in the heterogeneity observed in clinical symptoms of AD patients (Dujardin et al, 2020; Wesseling et al, 2020). It is important to consider the full spectrum of tau phosphorylation with age to better understand what role age-related molecular changes play in susceptibility to tau pathology
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