Hyperphosphorylated tau in Alzheimer's disease disseminates along pathways predicted by the Structural Model for Cortico‐cortical Connections

• Published in: Journal of comparative neurology (1911) 2024-05, Vol.532 (5), p.e25623-n/a
• Main Authors: Uceda‐Heras, Alicia, Aparicio‐Rodríguez, Gonzalo, García‐Cabezas, Miguel Ángel
• Format: Article
• Language: English
• Subjects: Aged; Aged, 80 and over; allocortex; Alzheimer Disease - metabolism; Alzheimer Disease - pathology; Alzheimer's disease; Cerebral cortex; Cerebral Cortex - metabolism; Cerebral Cortex - pathology; cortical type; Dementia disorders; eulaminate; Female; Humans; isocortex; Male; mesocortex; Middle Aged; Models, Neurological; neocortex; Neural Pathways - chemistry; Neural Pathways - metabolism; Neural Pathways - pathology; Neurodegenerative diseases; Neurons; Neurons - metabolism; Neurons - pathology; Phosphorylation; Tau protein; tau Proteins - metabolism; Temporal lobe
• ISSN: 0021-9967; 1096-9861; 1096-9861
• DOI: 10.1002/cne.25623

In Alzheimer´s disease (AD), hyperphosphorylated tau spreads along the cerebral cortex in a stereotypical pattern that parallels cognitive deterioration. Tau seems to spread transsynaptically along cortico‐cotical pathways that, according to synaptic tract‐tracing studies in nonhuman primates, have specific laminar patterns related to the cortical type of the connected areas. This relation is described in the Structural Model. In the present article, we study the laminar distribution of hyperphosphorylated tau, labeled with the antibody AT8, along temporal cortical types in postmortem human brains with different AD stages to test the predictions of the Structural Model. Brains from donors without dementia had scant AT8‐immunorreactive (AT8‐ir) neurons in allo‐, meso‐, and isocortical types. In early AD stages, the mesocortical dysgranular type, including part of the transentorhinal cortex, had the highest AT8 immunostaining and AT8‐ir neurons density. In advanced AD stages, AT8 immunostaining increased along the isocortical types until reaching the auditory koniocortex. Regarding laminar patterns, in early AD stages there were more AT8‐ir neurons in supragranular layers in each de novo involved neocortical type; in advanced AD stages, AT8‐ir neurons were equally distributed in supra‐ and infragranular layers. These AT8‐ir laminar patterns are compatible with the predictions of the Structural Model. In summary, we show that hyperphosphorylated tau initially accumulates in allo‐, meso‐, and isocortical types, offer a proof of concept for the validity of the Structural Model to predict synaptic pathway organization in the human cerebral cortex, and highlight the relevance of nonhuman primate tract‐tracing studies to understand human neuropathology. The Structural Model of Cortico‐cortical Connections, developed with synaptic tract‐tracing in nonhuman primates, predicts the laminar pattern of cortico‐cortical connections based on the cortical type of the connected areas. In Alzheimer's disease, hyperphosphorylated tau spreads along cortical areas in a predictable manner according to the Braak stages. We show that such spread follows synaptic pathways predicted by the Structural Model whose principles are applicable to the human cerebral cortex to infer laminar patterns of cortico‐cortical connections.