Loss of calbindin and rise in pT217-tau in aging monkey prefrontal cortical dendrites
Discuss this preprint
Start a discussion What are Sciety discussions?Listed in
This article is not in any list yet, why not save it to one of your lists.Abstract
INTRODUCTION
Tau pathology in Alzheimer’s disease preferentially afflicts excitatory neurons in the limbic and association cortices that utilize high levels of calcium signaling to perform cognitive operations. This includes the layer III pyramidal cells in the dorsolateral prefrontal cortex (dlPFC) that subserve higher cognition, which express the calcium-binding protein, calbindin, when young and healthy, but lose calbindin and develop tangles and degenerate in Alzheimer’s disease (AD). These data suggest that loss of calbindin may be associated with the emergence of tau pathology. However, the relationship between calbindin and early-stage, soluble tau pathology is challenging to study in human brains, as soluble pTau dephosphorylates within 15min postmortem. In contrast, the relationship between calbindin and soluble pT217-tau expression can be studied in aging macaques with naturally-occurring tau pathology, where perfusion fixation is possible to capture phosphorylation state in situ.
METHODS
The current study used multiple-label-immunofluorescence to label MAP2-positive dlPFC layer III pyramidal cells for calbindin and pT217-tau in macaque brains across the adult age span (8-34.5yrs). The study employed a semi-automated CellProfiler workflow to identify labeled pyramidal cell dendrites the cellular compartment where tau pathology begins in AD.
RESULTS
Calbindin expression decreased with age, while pT217Tau increased with age. Specifically, the ratio of calbindin/pT217-tau within a dendrite decreased with age, and was especially prominent in the aged macaques with long-term inflammatory disorders.
DISCUSSION
These data suggest that the loss of calbindin in dendrites with advancing age, and especially with inflammation, contributes to the rise of tau pathology and the risk of AD.
