Caspase-cleaved tau accumulation in neurodegenerative diseases associated with tau and α-synuclein pathology

Alzheimer's disease (AD), Pick's disease (PiD), progressive supranuclear palsy (PSP), corticobasal degeneration (CBD) and dementia with Lewy bodies (DLB) are diseases associated with the accumulation of tau or alpha-synuclein. In AD, beta-amyloid (A beta)-associated caspase activation and cleavage of tau at Asp(421) (Delta Tau) may be an early step in neurofibrillary tangle (NFT) formation. To examine whether Delta Tau accumulates in other diseases not characterized by extracellular A beta accumulation, we examined PiD, PSP, and CBD cases in comparison to those without extensive tau accumulation including frontotemporal lobar degeneration without Pick bodies (FTLD) and control cases. Additionally, we studied Delta Tau accumulation in DLB cases associated with intracellular alpha-synuclein. Delta Tau was observed in all disease cases except non-PiD FTLD and controls. These results demonstrate that the accumulation of Delta Tau may represent a common pathway associated with abnormal accumulation of intracellular tau or alpha-synuclein and may be relatively less dependent on the extracellular accumulation of A beta in non-AD dementias.