Localization of PDE4D, HCN1 channels, and mGluR3 in rhesus macaque entorhinal cortex may confer vulnerability in Alzheimer’s disease

Abstract

Alzheimer’s disease cortical tau pathology initiates in the layer II cell clusters of entorhinal cortex, but it is not known why these specific neurons are so vulnerable. Aging macaques exhibit the same qualitative pattern of tau pathology as humans, including initial pathology in layer II entorhinal cortex clusters, and thus can inform etiological factors driving selective vulnerability. Macaque data have already shown that susceptible neurons in dorsolateral prefrontal cortex express a “signature of flexibility” near glutamate synapses on spines, where cAMP-PKA magnification of calcium signaling opens nearby potassium and hyperpolarization-activated cyclic nucleotide-gated channels to dynamically alter synapse strength. This process is regulated by PDE4A/D, mGluR3, and calbindin, to prevent toxic calcium actions; regulatory actions that are lost with age/inflammation, leading to tau phosphorylation. The current study examined whether a similar “signature of flexibility” expresses in layer II entorhinal cortex, investigating the localization of PDE4D, mGluR3, and HCN1 channels. Results showed a similar pattern to dorsolateral prefrontal cortex, with PDE4D and mGluR3 positioned to regulate internal calcium release near glutamate synapses, and HCN1 channels concentrated on spines. As layer II entorhinal cortex stellate cells do not express calbindin, even when young, they may be particularly vulnerable to magnified calcium actions and ensuing tau pathology.

β1-adrenoceptor expression on GABAergic interneurons in primate dorsolateral prefrontal cortex: potential role in stress-induced cognitive dysfunction

“…Tissue from the dlPFC blocks of two young adult female macaques were used in this study (aged 8 and 10y). As described previously ( Datta et al, 2023 ), subjects were deeply anesthetized and transcardially perfused with 0.1M phosphate-buffered saline (PBS), followed by 4% paraformaldehyde and 0.05% glutaraldehyde in 0.1M PBS. Brains were removed, and a dorsolateral block was sliced at 60 μm on a vibratome (Leica, Norcross GA USA).…”