Tau deposition is associated with functional isolation of the hippocampus in aging

Harrison, Theresa M.; Maaß, Anne; Adams, Jenna N.; Du, Ruxu; Baker, Suzanne L.; Jagust, William J.

doi:10.1038/s41467-019-12921-z

Cited by 86 publications

(83 citation statements)

References 79 publications

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“…The pattern of Network 1 is like the joint of the anteriortemporal and posterior-medial system (30), which work interactively for encoding and retrieval memory (31,32). The reduced functional connectivity within Network 1 is consistent with evidence found in resting-state fMRI, both in AD and cognitively unimpaired amyloid-β + individuals (22,33). Importantly, we found the reduction speci cally in the maintenance and retrieval phase of memory.…”

Section: Network 1 Connectivity Is Predominantly Impaired In Adsupporting

confidence: 86%

Mapping of impaired functional connectivity during memory phases in Alzheimer's disease and its association with cortical β-amyloid

Zhang

et al. 2020

Preprint

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Abstract Background: Amnesia in Alzheimer's disease (AD) could be due to disrupted encoding, consolidation dysfunction, or an impairment in the retrieval of stored memory information. The different memory phases relate with different parts of functional brain systems. Methods: We combine task functional magnetic resonance imaging and amyloid positron emission tomography in 72 participants (36 AD and 36 controls), to investigate the relationship between memory performance, memory phase-locked functional connectivity, and cortical β-amyloid deposition.Results: We found that AD was mainly characterized by decreased functional connectivity in a new data-driven Network composed of regions from default mode network, limbic network and frontoparietal network during the memory maintenance and retrieval phase. Within the Network, AD had more regions with reduced connectivity during the retrieval phase than other phases, locating mainly in the medial prefrontal cortex, posterior cingulate cortex, middle temporal and inferior parietal cortex of left hemisphere. Furthermore, functional connectivity in the Network related to memory performance. Crucially, the magnitude of the Network connectivity reduction during retrieval negatively correlated with mean cortical β-amyloid, and this relationship mediated the relationship between cortical β-amyloid and memory performance.Conclusions: Our findings show that memory deficiency in AD relates with decreased connectivity in specific network and cortical β-amyloid only during retrieval phase. These findings help to map impaired functional connectivity during memory phases and explain the relationship between memory deficiency and cortical β-amyloid.

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Section: Network 1 Connectivity Is Predominantly Impaired In Adsupporting

confidence: 86%

Mapping of impaired functional connectivity during memory phases in Alzheimer's disease and its association with cortical β-amyloid

Zhang

et al. 2020

Preprint

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“…This process leads to the decline of cognitive abilities 59 , reducing the quality of life of elderly persons, whose population has increased over the last years. However, the cellular and molecular mechanisms leading to age-associated alterations are not completely clear 60 . Increasing evidence shows that synaptic dysfunction 61 and mitochondrial impairment 62 – 64 are considered early events during aging and in the pathogenesis of neurodegenerative disorders 63 .…”

Section: Discussionmentioning

confidence: 99%

“…When tau is abnormally phosphorylated it dissociates microtubules, losing its normal function and accumulating in neurons 60 , 82 , 83 . Tau hyperphosphorylation leads to aberrant self-assembly in insoluble aggregates, accompanied by synaptic dysfunction and neuronal death in a series of neurodegenerative diseases known as tauopathies 19 .…”

Section: Discussionmentioning

confidence: 99%

Pathologically phosphorylated tau at S396/404 (PHF-1) is accumulated inside of hippocampal synaptic mitochondria of aged Wild-type mice

Torres

Jara

Olesen

et al. 2021

Sci Rep

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Brain aging is a natural process characterized by cognitive decline and memory loss. This impairment is related to mitochondrial dysfunction and has recently been linked to the accumulation of abnormal proteins in the hippocampus. Age-related mitochondrial dysfunction could be induced by modified forms of tau. Here, we demonstrated that phosphorylated tau at Ser 396/404 sites, epitope known as PHF-1, is increased in the hippocampus of aged mice at the same time that oxidative damage and mitochondrial dysfunction are observed. Most importantly, we showed that tau PHF-1 is located in hippocampal mitochondria and accumulates in the mitochondria of old mice. Finally, since two mitochondrial populations were found in neurons, we evaluated tau PHF-1 levels in both non-synaptic and synaptic mitochondria. Interestingly, our results revealed that tau PHF-1 accumulates primarily in synaptic mitochondria during aging, and immunogold electron microscopy and Proteinase K protection assays demonstrated that tau PHF-1 is located inside mitochondria. These results demonstrated the presence of phosphorylated tau at PHF-1 commonly related to tauopathy, inside the mitochondria from the hippocampus of healthy aged mice for the first time. Thus, this study strongly suggests that synaptic mitochondria could be damaged by tau PHF-1 accumulation inside this organelle, which in turn could result in synaptic mitochondrial dysfunction, contributing to synaptic failure and memory loss at an advanced age.

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“…Prior evidence suggests that such tasks have potential for early detection of AD-related cognitive changes because 1) the task involves relational binding of objects and locations, which is impaired in prodromal AD and taps into the integrity of the entorhinal cortex and hippocampus, 34,68,[80][81][82] 2) a continuous metric may be a more sensitive index than categorical measures of retrieval, 50,67 and 3) memory fidelity relies on communication between hippocampus and cortical regions, which exhibit altered connectivity in the early course of AD. 1,16,24,[83][84][85][86][87][88][89][90] Previously, preclinical ε4 homozygotes at high risk of AD were impaired on a similar memory fidelity task, while heterozygotes were not. 52 Here, we aimed to increase sensitivity of such continuous report paradigms by increasing the to-be-recalled information per test display and by separating memory precision from retrieval success.…”

Section: Discussionmentioning

confidence: 99%

Memory precision of object-location binding is unimpaired inAPOEε4-carriers with spatial navigation deficits

Gellersen

Coughlan

Hornberger

et al. 2020

Preprint

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Research suggests that tests of memory fidelity, feature binding and spatial navigation are promising for early detection of subtle behavioural changes related to Alzheimer’s disease (AD). In the absence of longitudinal data, one way of testing the early detection potential of cognitive tasks is through the comparison of individuals at different genetic risk for AD. Most studies have done so using samples aged 70 years or older. Here, we tested whether memory fidelity of long-term object-location binding may be a sensitive marker even among cognitively healthy individuals in their mid-60s by comparing participants at low and higher risk based on presence of the ε4-allele of the apolipoprotein gene (n=26 ε3ε3 and n=20 ε3ε4 carriers). We used a continuous report paradigm in a visual memory task that required participants to recreate the spatial position of objects in a scene. We employed mixture modelling to estimate the two distinct memory processes that underpin the trial-by-trial variation in localisation errors: retrieval success which indexes the proportion of trials where participants recalled any information about an object’s position and the precision with which participants retrieved this information. Prior work has shown that these memory paradigms that separate retrieval success from precision are capable of detecting subtle differences in mnemonic fidelity even when retrieval success could not. Nonetheless, a Bayesian analysis found good evidence that ε3ε4 carriers did not remember fewer object locations (F(1, 42)=.450, p=.506, BF01=3.02), nor was their precision for the spatial position of objects reduced compared to ε3ε3 carriers (F(1, 42)=.12, p=.726, BF01=3.19). Importantly, ε3ε4-carriers from the same sample have previously been reported to exhibit wayfinding deficits in a spatial navigation task (Coughlan et al. 2019, PNAS, 116(19)). The sensitivity of memory fidelity tasks may therefore not extend to individuals with one ε4-allele in their early to mid-60s. These results provide further support to prior proposals that spatial navigation may be a sensitive marker for the earliest AD-dependent cognitive changes, even before episodic memory. More research in preclinical AD is needed to confirm this hypothesis by direct comparison of memory fidelity and spatial navigation tasks.

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Tau deposition is associated with functional isolation of the hippocampus in aging

Cited by 86 publications

References 79 publications

Mapping of impaired functional connectivity during memory phases in Alzheimer's disease and its association with cortical β-amyloid

Mapping of impaired functional connectivity during memory phases in Alzheimer's disease and its association with cortical β-amyloid

Pathologically phosphorylated tau at S396/404 (PHF-1) is accumulated inside of hippocampal synaptic mitochondria of aged Wild-type mice

Memory precision of object-location binding is unimpaired inAPOEε4-carriers with spatial navigation deficits

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