Human amygdala involvement in Alzheimer's disease revealed by stereological and dia‐PASEF analysis

Alzheimer's disease (AD) is characterized by the accumulation of pathological amyloid‐β (Aβ) and Tau proteins. According to the prion‐like hypothesis, both proteins can seed and disseminate through brain regions through neural connections and glial cells. The amygdaloid complex (AC) is involved early in the disease, and its widespread connections with other brain regions indicate that it is a hub for propagating pathology. To characterize changes in the AC as well as the involvement of neuronal and glial cells in AD, a combined stereological and proteomic analysis was performed in non‐Alzheimer's disease and AD human samples. The synaptic alterations identified by proteomic data analysis could be related to the volume reduction observed in AD by the Cavalieri probe without neuronal loss. The pathological markers appeared in a gradient pattern with the medial region (cortical nucleus, Co) being more affected than lateral regions, suggesting the relevance of connections in the distribution of the pathology among different brain regions. Generalized astrogliosis was observed in every AC nucleus, likely related to deposits of pathological proteins. Astrocytes might mediate phagocytic microglial activation, whereas microglia might play a dual role since protective and toxic phenotypes have been described. These results highlight the potential participation of the amygdala in the disease spreading from/to olfactory areas, the temporal lobe and beyond. Proteomic data are available via ProteomeXchange with identifier PXD038322. A combined stereological and proteomic analysis revealed amygdala volume reduction linked to synaptic dysfunction in Alzheimer''s disease samples. The pathological markers gradient suggested the relevance of connections in the distribution of the pathology among different brain regions. Extended astrogliosis, likely as response to pathologic deposits, could mediate phagocytic microglial activation. Microglia might play a dual role since protective and toxic phenotypes have been described. In conclusion, amygdala might promote the spreading of pathology from/to olfactory areas, the temporal lobe and beyond.