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Spreading of Alzheimer tau seeds is enhanced by aging and template matching with limited impact of amyloid-β.

ABSTRACT: In Alzheimer's disease (AD), deposition of pathological tau and amyloid-β (Aβ) drive synaptic loss and cognitive decline. The injection of misfolded tau aggregates extracted from human AD brains drives templated spreading of tau pathology within WT mouse brain. Here, we assessed the impact of Aβ copathology, of deleting loci known to modify AD risk (Ptk2b, Grn, and Tmem106b) and of pharmacological intervention with an Fyn kinase inhibitor on tau spreading after injection of AD tau extracts. The density and spreading of tau inclusions triggered by human tau seed were unaltered in the hippocampus and cortex of APPswe/PSEN1ΔE9 transgenic and App^NL-F/NL-F knock-in mice. In mice with human tau sequence replacing mouse tau, template matching enhanced neuritic tau burden. Human AD brain tau-enriched preparations contained aggregated Aβ, and the Aβ coinjection caused a redistribution of Aβ aggregates in mutant AD model mice. The injection-induced Aβ phenotype was spatially distinct from tau accumulation and could be ameliorated by depleting Aβ from tau extracts. These data suggest that Aβ and tau pathologies propagate by largely independent mechanisms after their initial formation. Altering the activity of the Fyn and Pyk2 (Ptk2b) kinases involved in Aβ-oligomer-induced signaling, or deleting expression of the progranulin and TMEM106B lysosomal proteins, did not alter the somatic tau inclusion burden or spreading. However, mouse aging had a prominent effect to increase the accumulation of neuritic tau after injection of human AD tau seeds into WT mice. These studies refine our knowledge of factors capable of modulating tau spreading.

SUBMITTER: Nies SH

PROVIDER: S-EPMC8477193 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Current approaches to the early detection of Alzheimer's disease (AD) rely upon classifying individuals as "positive" or "negative" for biomarkers related to the core pathology of ?-amyloid (A?). However, the accumulation of A? begins slowly, years before biomarkers become abnormal. We used longitudinal [11C] Pittsburgh Compound B PET scanning and neuropsychological assessment to investigate the earliest changes in AD pathology and how it affects memory in cognitively normal older humans (N = 71; mean age 75 years; 35% male). We used [18F] AV-1451 PET scanning at the end of the observation period to measure subsequent tau deposition in a subset of our sample (N = 37). We found evidence for an inverted-U relationship between baseline A? levels and A? slope in asymptomatic older adults, suggesting a slowing of A? accumulation even in cognitively normal adults. In participants who were nominally amyloid negative, both the rate of amyloid accumulation and the baseline levels of A? predicted early tau deposition in cortical Braak regions associated with AD. Amyloid measures were only sensitive to memory decline as baseline levels of A? increased, suggesting that pathological accumulation occurs before impacting memory. These findings support the necessity of early intervention with amyloid-lowering therapies even in those who are amyloid negative.SIGNIFICANCE STATEMENT The progressive nature of Alzheimer's disease (AD) necessitates the earliest possible detection of pathological or cognitive change if disease progression is to be slowed. We examined cognitively normal older adults in whom AD pathology is starting to develop, with the goal of early detection of AD pathology or cognitive changes. We found amyloid measures to be sensitive early on in predicting subsequent early tau deposition. Further, it appears that rates of amyloid accumulation already begin to slow in preclinical AD, suggesting that it is a relatively late stage of AD progression. Thus, it is crucial to examine older adults early, before amyloid levels have saturated, to intervene to slow disease progression.

Project description:BackgroundMisfolding of microtubule-associated protein tau (MAPT) within neurons into neurofibrillary tangles is an important pathological feature of Alzheimer's disease (AD). Tau pathology correlates with cognitive decline in AD and follows a stereotypical anatomical course; several recent studies indicate that tau pathology spreads inter-neuronally via misfolded tau "seeds." Previous research has focused on neurons as the source of these tau seeds. However, recent studies as well as the data contained herein suggest that microglia, the resident immune cells of the central nervous system, play a direct role in the spread of tau pathology.MethodsPrimary adult microglia were isolated from human AD cases and the rTg4510 tauopathy mouse model and used for analysis of gene expression, tau protein by Simoa technology, and quantification of tau seeding using a highly sensitive fluorescence resonance energy transfer (FRET) biosensing cell line for tau seeding and aggregation.ResultsHere, we show that microglia isolated from both human tauopathy and AD cases and the rTg4510 tauopathy mouse model stably contain tau seeds, despite not synthesizing any tau. Microglia releases these tau seeds in vitro into their conditioned media (CM). This suggests that microglia have taken up tau but are incapable of entirely neutralizing its seeding activity. Indeed, when in vitro microglia are given media containing tau seeds, they reduce (but do not eliminate) tau seeding. When microglia are treated with inflammagens such as lipopolysaccharide (LPS), interleukin-1β (IL1β), tumor necrosis factor α (TNFα), or amyloid-β, their ability to reduce tau seeding is unchanged and these factors do not induce seeding activity on their own.ConclusionsOverall, these data suggest that microglia have a complex role: they are capable of taking up and breaking down seed competent tau, but do so inefficiently and could therefore potentially play a role in the spread of tau pathology.

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Spreading of Alzheimer tau seeds is enhanced by aging and template matching with limited impact of amyloid-β.

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