Tau oligomers impair memory and induce synaptic and mitochondrial dysfunction in wild-type mice

Lasagna‐Reeves, Cristian A.; Castillo-Carranza, Diana L.; Sengupta, Urmi; Clos, Audra L.; Jackson, George R.; Kayed, Rakez

doi:10.1186/1750-1326-6-39

Cited by 504 publications

(433 citation statements)

References 84 publications

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“…Each fraction was subjected to a panel of commercially available antibodies detecting human αSyn (LB509, 4B12), mouse/human αSyn (4D6), phosphorylated and misfolded αSyn (pS129-αSyn and Syn514), and to a panel of antibodies generated to detect oligomeric and aggregated amyloid proteins (A11, OC, Officer), including o-αSyn (Syn33, F8H7) (23). We also included analyses with the 6E10 antibody detecting Aβ [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16] to determine whether the putative o-αSyn might be coupled to Aβ as a hybrid oligomer (24). Although a clear signal was detected in fraction 38, likely because of soluble APP or Aβ protofibrils, the pattern obtained with 6E10 was distinct from those found with αSyn antibodies.…”

Section: Resultsmentioning

confidence: 99%

“…α-synuclein | oligomer | memory | Alzheimer's disease | synapsins A lthough abnormal protein aggregates in the form of amyloid plaques, neurofibrillary tangles, and Lewy bodies (LB) characterize neurodegenerative disorders, such as Alzheimer's disease (AD) and Parkinson's disease, an accumulating body of evidence indicates that soluble multimeric species of these proteins, also known as oligomers, might underlie the deleterious cascades of molecular changes ultimately resulting in these chronic brain disorders (1)(2)(3). In this context, we define soluble endogenous amyloid oligomers as multimeric assemblies that (i) remain soluble in aqueous buffers following ultracentrifugation, (ii) are SDS-resistant following tissue lysis, (iii) are separated in liquid-phase chromatography, and (iv) are immunoreactive to at least two different antibodies for that amyloid molecule.…”

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confidence: 99%

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Selective lowering of synapsins induced by oligomeric α-synuclein exacerbates memory deficits

Larson

Greimel

Amar

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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Mounting evidence indicates that soluble oligomeric forms of amyloid proteins linked to neurodegenerative disorders, such as amyloid-β (Aβ), tau, or α-synuclein (αSyn) might be the major deleterious species for neuronal function in these diseases. Here, we found an abnormal accumulation of oligomeric αSyn species in AD brains by custom ELISA, size-exclusion chromatography, and nondenaturing/denaturing immunoblotting techniques. Importantly, the abundance of αSyn oligomers in human brain tissue correlated with cognitive impairment and reductions in synapsin expression. By overexpressing WT human αSyn in an AD mouse model, we artificially enhanced αSyn oligomerization. These bigenic mice displayed exacerbated Aβ-induced cognitive deficits and a selective decrease in synapsins. Following isolation of various soluble αSyn assemblies from transgenic mice, we found that in vitro delivery of exogenous oligomeric αSyn but not monomeric αSyn was causing a lowering in synapsin-I/II protein abundance. For a particular αSyn oligomer, these changes were either dependent or independent on endogenous αSyn expression. Finally, at a molecular level, the expression of synapsin genes SYN1 and SYN2 was down-regulated in vivo and in vitro by αSyn oligomers, which decreased two transcription factors, cAMP response element binding and Nurr1, controlling synapsin gene promoter activity. Overall, our results demonstrate that endogenous αSyn oligomers can impair memory by selectively lowering synapsin expression.α-synuclein | oligomer | memory | Alzheimer's disease | synapsins

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Section: Resultsmentioning

confidence: 99%

mentioning

confidence: 99%

Selective lowering of synapsins induced by oligomeric α-synuclein exacerbates memory deficits

Larson

Greimel

Amar

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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“…These types of studies will benefit greatly from new in vivo staining compounds that differentially bind soluble, prefibrillar, and aggregated tau. Even within these limitations, however, our present findings call into question therapeutic strategies aimed at preventing or disrupting fibrillar tau deposits (30), which may indeed sequester more toxic soluble tau species (31,32).…”

Section: Significancementioning

confidence: 95%

Neurofibrillary tangle-bearing neurons are functionally integrated in cortical circuits in vivo

Kuchibhotla

Wegmann

Kopeikina

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

179

136

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Alzheimer's disease (AD) is pathologically characterized by the deposition of extracellular amyloid-β plaques and intracellular aggregation of tau protein in neurofibrillary tangles (NFTs) (1, 2). Progression of NFT pathology is closely correlated with both increased neurodegeneration and cognitive decline in AD (3) and other tauopathies, such as frontotemporal dementia (4,5). The assumption that mislocalization of tau into the somatodendritic compartment (6) and accumulation of fibrillar aggregates in NFTs mediates neurodegeneration underlies most current therapeutic strategies aimed at preventing NFT formation or disrupting existing NFTs (7,8). Although several disease-associated mutations cause both aggregation of tau and neurodegeneration, whether NFTs per se contribute to neuronal and network dysfunction in vivo is unknown (9). Here we used awake in vivo two-photon calcium imaging to monitor neuronal function in adult rTg4510 mice that overexpress a human mutant form of tau (P301L) and develop cortical NFTs by the age of 7-8 mo (10). Unexpectedly, NFT-bearing neurons in the visual cortex appeared to be completely functionally intact, to be capable of integrating dendritic inputs and effectively encoding orientation and direction selectivity, and to have a stable baseline resting calcium level. These results suggest a reevaluation of the common assumption that insoluble tau aggregates are sufficient to disrupt neuronal function.paired helical filaments | tau pathology | neuronal networks N eurofibrillary tangles (NFTs) containing aggregated tau protein (1) have long been considered key players in the progressive neural dysfunction and neurodegeneration observed in Alzheimer's disease (AD) (2, 3) and other tauopathies (4, 5). It is commonly assumed that NFT-bearing neurons exhibit deficits in synaptic integration and eventually lead to neurodegeneration (11,12). However, the actual functional properties of NFT-bearing neurons in intact neural circuits have not been explored previously (13). We addressed this question directly using awake in vivo two-photon calcium imaging in a mouse model of NFT formation (rTg4510) by applying recently developed imaging approaches allowing for single-neuron-level and population-level assessment of neural activity in awake mice (14). Because two-photon calcium imaging allows for measurement of response properties in many neurons simultaneously, we were able to directly isolate the impact of NFT deposition in a neuronal microcircuit by evaluating population-level network dynamics and, more specifically, by differentiating the function of individual NFT-bearing and neighboring non-NFT-bearing neurons.To assess the functional properties of neurons in the visual cortex, we used a genetically encoded ratiometric calcium indicator, yellow cameleon 3.6 (YC3.6), packaged in an adenoassociated viral vector (15,16). To assess functional responses, we exploited the well-characterized functional architecture of visual cortex whereby neurons in mouse visual cortex modulate their activity d...

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“…Because tau and p-tau oligomers may contribute to synaptic dysfunction and loss, 8,27,29,58 we next examined timing of the appearance of synaptic p-tau for disease stage and amyloid pathology using the set of staged human samples, including nondemented HPCs. P-2 samples were immunolabeled for tau with the use of three antibodies: one directed against total tau (HT7) and two specific for p-tau (PHF-1 and pS 422 ).…”

Section: Synaptic P-tau Is Not Elevated Until Late-stage Ad In Parietmentioning

confidence: 99%

Synaptic Amyloid-β Oligomers Precede p-Tau and Differentiate High Pathology Control Cases

Bilousova

Miller

Poon

et al. 2016

The American Journal of Pathology

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Amyloid-b (Ab) and hyperphosphorylated tau (p-tau) aggregates form the two discrete pathologies of Alzheimer disease (AD), and oligomeric assemblies of each protein are localized to synapses. To determine the sequence by which pathology appears in synapses, Ab and p-tau were quantified across AD disease stages in parietal cortex. Nondemented cases with high levels of AD-related pathology were included to determine factors that confer protection from clinical symptoms. Flow cytometric analysis of synaptosome preparations was used to quantify Ab and p-tau in large populations of individual synaptic terminals. Soluble Ab oligomers were assayed by a single antibody sandwich enzyme-linked immunosorbent assay. Total in situ Ab was elevated in patients with early-and late-stage AD dementia, but not in high pathology nondemented controls compared with age-matched normal controls. However, soluble Ab oligomers were highest in early AD synapses, and this assay distinguished early AD cases from high pathology controls. Overall, synapse-associated p-tau did not increase until late-stage disease in human and transgenic rat cortex, and p-tau was elevated in individual Ab-positive synaptosomes in early AD. These results suggest that soluble oligomers in surviving neocortical synaptic terminals are associated with dementia onset and suggest an amyloid cascade hypothesis in which oligomeric Ab drives phosphorylated tau accumulation and synaptic spread. These results indicate that antiamyloid therapies will be less effective once p-tau pathology is developed. (Am J Pathol 2016, 186: 185e198; http://dx.doi.org/10.1016/j.ajpath.2015 A large body of evidence indicates that soluble oligomers of amyloid-b (Ab) are the primary toxic peptides that initiate downstream tau pathology in the amyloid cascade hypothesis of Alzheimer disease (AD). 1,2 However, the time course and severity of AD dementia have been generally found to correlate with neurofibrillary tangle development rather than plaque appearance, 3e8 although a few studies have linked plaques with early cognitive decline. 9e12 Soluble oligomeric

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Tau oligomers impair memory and induce synaptic and mitochondrial dysfunction in wild-type mice

Cited by 504 publications

References 84 publications

Selective lowering of synapsins induced by oligomeric α-synuclein exacerbates memory deficits

Selective lowering of synapsins induced by oligomeric α-synuclein exacerbates memory deficits

Neurofibrillary tangle-bearing neurons are functionally integrated in cortical circuits in vivo

Synaptic Amyloid-β Oligomers Precede p-Tau and Differentiate High Pathology Control Cases

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