To investigate the structural characteristics of tau filaments in Alzheimer's disease neuropathologic change (ADNC) with co-morbid limbic-predominant age-related TDP-43 encephalopathy neuropathologic change (LATE-NC).
Approach:
Cryo-electron microscopy analysis: Analyzed patient-derived tau filaments in ADNC to identify structural polymorphs and their relationship with co-morbid LATE-NC.
Immunostaining and molecular content extraction: Performed phosphorylated tau, Aβ, and phosphorylated TDP-43 immunostaining, followed by extraction of sarkosyl-insoluble material for further analysis.
Cortical sampling: Conducted additional cortical sampling to identify CTE lesions based on consensus guidelines.
Key Findings:
Two structural polymorphs of tau were identified: paired helical filament (PHF) and straight filament (SF), both exhibiting the AD-fold.
Distinct tau conformations resembling chronic traumatic encephalopathy (CTE) were observed in AD + LATE-NC cases.
One case exhibited a CTE lesion, while the other did not meet CTE-NC criteria despite the presence of CTE-fold tau.
Interpretation:
Limitations:
Only two cases were analyzed, limiting the generalizability of findings.
CTE lesions were sparse and difficult to identify, potentially leading to underdiagnosis.
