Amyloid-β plaques enhance Alzheimer's brain tau-seeded pathologies by facilitating neuritic plaque tau aggregation

He, Zhuohao; Guo, Jing; McBride, Jennifer D.; Narasimhan, Sneha; Kim, Hyesung; Changolkar, Lakshmi; Zhang, Bin; Gathagan, Ronald J.; Yue, Cuiyong; Dengler, Christopher G.; Stieber, Anna; Nitla, Magdalena; Coulter, Douglas A.; Abel, Ted; Brunden, Kurt R.; Trojanowski, John Q.; Lee, Virginia M.‐Y.

doi:10.1038/nm.4443

Cited by 497 publications

(522 citation statements)

References 40 publications

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“…It is also possible that the rate of tau accumulation slows over time, similar to amyloid accumulation. [40][41][42] Thus, we hypothesized that PiB + OA would have higher rates of FTP accumulation than PiB − OA. Previous work has shown that cross-sectional FTP is associated with cross-sectional atrophy patterns in AD, 10,21 but our study extends these findings by revealing that FTP longitudinal accumulation occurs in regions that are relatively less affected by atrophy.…”

Section: Discussionmentioning

confidence: 99%

Longitudinal tau accumulation and atrophy in aging and alzheimer disease

Harrison

Joie

Maaß

et al. 2019

Annals of Neurology

224

231

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Objective: To determine the rate of tau accumulation in healthy older adults (OA) and patients with Alzheimer disease (AD), as well as the relationship of tau accumulation to cortical atrophy. Methods: Two longitudinal flortaucipir (FTP) positron emission tomography (PET) and magnetic resonance imaging (MRI) scans were acquired from 42 OA (21 Pittsburg compound B [PiB] + , age = 77.6 AE 4.6 years, 25 female [F]/17 male [M]) and 19 PiB + patients with AD (age = 63.1 AE 10.3 years, 12 F/7 M) over 1 to 3 years of follow-up. FTP change, structural MRI measures of atrophy, and cross-modal correlations were examined on a voxelwise level. Regional annual percentage change in FTP was also calculated. Results: Voxelwise FTP change in AD showed the greatest increases in lateral and medial frontal lobes. Atrophy over the same interval was more widespread and included posteromedial cortical areas, where tau accumulation rates were lower. In OA, FTP binding increased in bilateral temporal lobe and retrosplenial cortex, accompanied by atrophy in the same regions. There were no associations between voxelwise change in FTP and sex, PiB, or APOE. Regional FTP significantly increased at follow-up in OA and patients with AD. Mixed effects models showed greater FTP increases in AD compared to OA, and no differences within OA based on PiB status. Interpretation: Our findings indicate that tau accumulates even in amyloid-negative healthy OA and this process can be measured with in vivo tau-PET. In OA, tau accumulation and atrophy share a similar topography. In AD, tau increases more rapidly and accumulation occurs in frontal regions that are not yet undergoing significant atrophy.

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Section: Discussionmentioning

confidence: 99%

Longitudinal tau accumulation and atrophy in aging and alzheimer disease

Harrison

Joie

Maaß

et al. 2019

Annals of Neurology

224

231

View full text Add to dashboard Cite

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“…2), an association not seen at high Thal phases. These results are correlative and not causal; nonetheless, the recent demonstration that pathological tau isolated from AD brain increases the plaque burden and induces widespread tau pathology in animal models implies that pathological tau interacts with the Aβ plaque environment to drive the increase in tau and Aβ pathology [17]. In particular, the increase from Braak stage III to IV may represent an important transition from age-associated pathology to dementia-associated pathology.…”

Section: Discussionmentioning

confidence: 99%

Non-Alzheimer’s contributions to dementia and cognitive resilience in The 90+ Study

et al. 2018

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The diagnosis of Alzheimer's disease (AD) in the oldest-old is complicated by the increasing prevalence of age-related neurofibrillary tangles, plaques and non-AD pathologies such as cerebrovascular disease (CVD), hippocampal sclerosis (HS), aging-related tau astrogliopathy (ARTAG), as well as TDP-43 and Lewy pathology. The contribution of these non-AD pathologies to dementia and cognitive resilience is unclear. We assessed the level of AD neuropathologic change (ADNPC) and non-AD pathology in 185 participants enrolled in The 90+ Study with available cognitive assessments and brain tissue. Logistic regression models-adjusting for age, sex and education-determined the association between each pathology and dementia or between subgroups. 53% had dementia, primarily AD or mixed AD; 23% had cognitive impairment without dementia (CIND); 23% were not impaired. Both AD and non-AD pathology was prevalent. 100% had tangles, 81% had plaques, and both tangles and plaques associated with dementia. ARTAG distributed across limbic (70%), brainstem (39%) and cortical regions (24%). 49% had possible CVD and 26% had definite CVD, while HS was noted in 15%. Cortical ARTAG, CVD and HS were each associated with dementia, but limbic and brainstem ARTAGs were not. TDP-43 and Lewy pathologies were found in 36 and 17% and both associated with dementia. No pathology distinguished CIND and the not impaired. By NIA-AA criteria and dementia status, the cohort was subdivided into four groups: those with minimal ADNPC included the not dementia (ND) and Not AD dementia groups; and those with significant ADNPC included the Resilient without dementia and AD dementia groups. Compared to the ND group, the Not AD dementia group had more HS, cortical ARTAG, TDP-43, and Lewy pathology. Compared to the AD dementia group, the Resilient group had less CVD, no HS and less cortical ARTAG, TDP-43 and Lewy pathology. Our findings imply that reductions in non-AD pathologies including CVD contribute to cognitive resilience in the oldest-old.

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“…Thus, the role of tau in mediating axonal damage and Aβ deposition seems to be linked to gain of function within the unique Aβ plaque environment. In a recent study, it was shown that tau initially aggregates in dystrophic neurites surrounding Aβ plaques (He et al , ). It is tempting to speculate that such initially formed tau species might locally compromise microtubules and thereby axonal transport of BACE1 and other proteins.…”

Section: Discussionmentioning

confidence: 99%

Tau deletion reduces plaque‐associated BACE 1 accumulation and decelerates plaque formation in a mouse model of Alzheimer's disease

et al. 2019

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In Alzheimer's disease, BACE1 protease initiates the amyloidogenic processing of amyloid precursor protein (APP) that eventually results in synthesis of β‐amyloid (Aβ) peptide. Aβ deposition in turn causes accumulation of BACE1 in plaque‐associated dystrophic neurites, thereby potentiating progressive Aβ deposition once initiated. Since systemic pharmacological BACE inhibition causes adverse effects in humans, it is important to identify strategies that specifically normalize overt BACE1 activity around plaques. The microtubule‐associated protein tau regulates axonal transport of proteins, and tau deletion rescues Aβ‐induced transport deficits in vitro. In the current study, long‐term in vivo two‐photon microscopy and immunohistochemistry were performed in tau‐deficient APPPS1 mice. Tau deletion reduced plaque‐associated axonal pathology and BACE1 accumulation without affecting physiological BACE1 expression distant from plaques. Thereby, tau deletion effectively decelerated formation of new plaques and reduced plaque compactness. The data revealed that tau reinforces Aβ deposition, presumably by contributing to accumulation of BACE1 in plaque‐associated dystrophies. Targeting tau‐dependent mechanisms could become a suitable strategy to specifically reduce overt BACE1 activity around plaques, thereby avoiding adverse effects of systemic BACE inhibition.

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Amyloid-β plaques enhance Alzheimer's brain tau-seeded pathologies by facilitating neuritic plaque tau aggregation

Cited by 497 publications

References 40 publications

Longitudinal tau accumulation and atrophy in aging and alzheimer disease

Longitudinal tau accumulation and atrophy in aging and alzheimer disease

Non-Alzheimer’s contributions to dementia and cognitive resilience in The 90+ Study

Tau deletion reduces plaque‐associated BACE 1 accumulation and decelerates plaque formation in a mouse model of Alzheimer's disease

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