In:
Alzheimer's & Dementia, Wiley, Vol. 16, No. S3 ( 2020-12)
Abstract:
Alzheimer’s disease is mainly characterized by amyloid β (Aβ) plaques and tau neurofibrillary tangles (NFTs). The amyloid cascade hypothesis provides a hypothetical link between these two proteinopathies and posits that Aβ can trigger tauopathy. Method To understand the temporal relationship between Aβ and tau and also to probe whether specific forms of misfolded tau preferentially interact with Aβ to induce the neurodegenerative cascade, we used an adeno‐associated model (AAV) of tauopathy combined with the TgCRND8 mouse model of Aβ deposition. We used three different types of tau variants in TgCRND8 mice – wild type (WT) tau, FTD‐associated P301L mutant tau and Pick’s disease‐associated S320F mutant tau. In prior studies, we demonstrated that while both WT and P301L tau expression results in accumulation of soluble phosphorylated tau in nontransgenic mice, only the S320F mutant readily formed insoluble intracellular NFTs allowing us to test the relative vulnerability of the Aβ mouse model to different types of misfolded tau. Result In the first cohort, we injected the AAV‐tau constructs into the brains of neonatal TgCRND8 mice. At 3 months post‐injection, when Aβ deposits first begin to appear, we found ‐ that expression of S320F tau produced NFT and surprisingly also exacerbated Aβ deposition. Expression of WT or P301L tau had no effect. The intracellular tau pathology in all these mice resembled the patterns observed in nontransgenic CRND8 littermates, suggesting no obvious cooperativity between Aβ and tau. In the second cohort, we delivered these AAV‐tau in the hippocampus of adult TgCRND8 mice with pre‐existing Aβ pathology and analyzed after three months of AAV expression. Here, we observed that the presence of pre‐existing Aβ induced formation of NFT pathology in the P301L tau expressing mice but not in the WT tau expressing mice. The levels of tau pathology from expression of S320F tau induced NFTs were essentially similar to that found in the first cohort that was injected neonatally. Conclusion Taken together, our data demonstrate gradations in the ability of pre‐existing Aβ deposits to secondarily induce tau misfolding, with the P301L tau variant showing the greatest response.
Type of Medium:
Online Resource
ISSN:
1552-5260
,
1552-5279
Language:
English
Publisher:
Wiley
Publication Date:
2020
detail.hit.zdb_id:
2201940-6
