Vulnerable neuronal subsets in Alzheimer's and Pick's disease are distinguished by their τ isoform distribution and phosphorylation

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Abstract
Aggregated τ proteins constitute the basic matrix of neuronal inclusions specific to numerous neurodegenerative disorders. Monodimensional and two‐dimensional Western blot analyses performed on cortical brain homogenates allowed discrimination between disease‐specific τ protein profiles. These observations raised the issue of the physiopathological significance of such specificities. Alzheimer's disease (AD) pathological τ proteins (PTPs) (τ 74, 69, 55) were compared with those of Pick's disease (PiD) (τ 64, 55) using a panel of antibodies against peptidic sequences of τ isoforms corresponding to exons 2, 3, and 10. AD and PiD could then be critically differentiated by the absence of translated τ isoforms with exon 10 in PiD PTPs, along with the absence of the phosporylation site on Ser262. Immunohistochemical studies corroborate these findings. Indeed, Pick bodies were strongly immunostained by an anti‐“exon 2” antibody but failed to reveal any anti‐exon 10 reactive epitope. Tangles in AD contained exon 2, 3, and 10 epitopes. Altogether, our results demonstrated that Pick bodies develop within specific neuronal subsets that express specific patterns of τ isoforms lacking exon 10 peptidic sequence. We conclude that neurodegenerative disorders imply attrition of selectively vulnerable neuronal subsets, a process revealed, and may be sustained by specific τ isoform patterns.