Brain Aging and Dysregulated Protein Phosphorylation in Alzheimer Disease

Altered phosphorylation patterns of some proteins may have implications for sporadic Alzheimer disease (sAD), according to results of a postmortem tissue analysis published in Brain Pathology.

Study researchers obtained postmortem samples from the Institute of Neuropathology HUB-ICO-IDIBELL Biobank in Spain. Tissue processing was between 3 hours and 13 hours and 40 minutes after death. Researchers then assessed samples by phosphoproteomic analysis, immunohistochemistry, and immunofluorescence.

Patients with AD (pathologic cases; n=15) were in neurofibrillary tangle (NFT) Braak stage I to II (n=5), III to IV (n=5), and V to VI (n=5). Controls (n=9) had not been diagnosed with any neurologic or psychiatric conditions. All samples were obtained from individuals aged between 33 and 92 years.

In the entorhinal cortex, study researchers observed a total of 230 proteins and 214 phosphoproteins to be dysregulated, specifically 57 and 65 at NFT stage I to II; 89 and 135 at stage III to IV; and 136 and 118 at stage V to VI, respectively. The patterns of hyper- or hypophosphorylation on the basis of NFT stage were not apparent.

There were between 10 and 40 common phosphoproteins across the NFT stages. Findings indicated no overlap between dysregulated proteins and phosphoproteins.

A gene ontology analysis of dysregulated proteins in the entorhinal cortex identified the relevant terms of synapse organization, nervous system development, chemical synaptic transmission, neuronal systems, regulation of membrane potential, synaptic vesicle cycle, regulation of vesicle-mediated transport, and dendritic development, among others.

In the frontal cortex, a total of 82 proteins and 167 phosphoproteins were dysregulated, specifically 23 and 81 at NFT stage I to II; 31 and 92 at stage III to IV; and 37 and 79 at stage V to VI, respectively. Study researchers noted no apparent patterns of hyper- or hypophosphorylation on the basis of NFT stage.

Across the NFT stages, there were 14 common phosphoproteins between stages V to VI and III to IV and 15 between III to IV and I to II. Findings indicated no overlap between dysregulated proteins and phosphoproteins.

A gene ontology analysis of dysregulated proteins in the frontal cortex identified the relevant terms of synapse organization, axon guidance, neurexins, neuroligins, chemical synaptic transmission, neuronal systems, and dendrite development, among others.

This study was limited by concomitant pathologies among the patients and the postmortem delay from death to tissue processing.

These findings confirmed previous studies which identified altered protein phosphorylation in the entorhinal and frontal cortices among patients with advanced AD and for provided “for the first time robust data on the first and middle stages of NFT pathology linked to AD.” It remains unclear what role the dysregulation of proteins has on normal aging or sAD and requires additional study.

Reference

Ferrer I, Andrés-Benito P, Ausín K, et al. Dysregulated protein phosphorylation: A determining condition in the continuum of brain aging and Alzheimer’s disease. Brain Pathol. 2021;e12996. doi:10.1111/bpa.12996