Differential expression of tau species and the association with cognitive decline and synaptic loss in Alzheimer's disease

• Published in: Alzheimer's & dementia Vol. 18; no. 9; pp. 1602 - 1615
• Main Authors: Saroja, Sivaprakasam R., Sharma, Abhijeet, Hof, Patrick R., Pereira, Ana C.
• Format: Journal Article
• Language: English
• Published: United States 01.09.2022
• Subjects: Alzheimer Disease - pathology; Alzheimer's disease; Cognitive Dysfunction - metabolism; cognitive impairment; extracellular vesicles and Serpina3n; Humans; neurodegeneration; Neurofibrillary Tangles - pathology; Plaque, Amyloid - pathology; Protein Isoforms - metabolism; synaptic loss; tau pathology; tau Proteins - metabolism; neurodegeneration; tau pathology; extracellular vesicles and Serpina3n; cognitive impairment; synaptic loss; Alzheimer's disease
• ISSN: 1552-5260; 1552-5279; 1552-5279
• DOI: 10.1002/alz.12518

Pathological tau proteins in patients with Alzheimer's disease (AD) mainly accumulate in the form of neurofibrillary tangles (NFTs) and neuritic plaques (NPs). However, the molecular properties of tau species present in NFTs and NPs are not known. We tested the hypothesis that tau species within NFT‐predominant tissue (NFT_AD) are distinct and more toxic than those in NP‐predominant tissue (NP_AD). We analyzed the tau species from post mortem prefrontal cortical brains of NFT_AD and NP_AD. Compared to NP_AD, NFT_AD displayed highly phosphorylated tau oligomers, possessed tau oligomers in extracellular vesicles, and the 3‐repeat (3R) and 4‐repeat (4R) isoforms were differentially expressed between the groups. Comparison of tau proteins isolated from NFT‐ versus NP‐AD subjects demonstrated higher tau seeding activity in NFT subjects and a greater degree of inducing synaptic loss in cultured neurons. We propose that tau species from NFT‐predominant tissues possess greater levels of degenerative properties, thereby causing synaptic loss and cognitive decline.