Accumulation of Pathological Tau Species and Memory Loss in a Conditional Model of Tauopathy

Berger, Zdenek; Roder, Hanno M.; Hanna, Amanda; Carlson, A. J.; Rangachari, Vijayaraghavan; Yue, Mei; Wszołek, Zbigniew K.; Ashe, Karen H.; Knight, Joshua; Dickson, Dennis W.; Andorfer, Cathy A.; Rosenberry, Terrone L.; Lewis, Jada; Hutton, Mike; Janus, Christopher

doi:10.1523/jneurosci.0587-07.2007

Cited by 450 publications

(429 citation statements)

References 43 publications

(73 reference statements)

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“…Thus, NFTs are not required for and may not be the primary cause of neurotoxicity and cognitive dysfunction. In fact, levels of early Tau multimeric aggregates that preceded NFTs correlated with memory deficits in transgenic mice that overexpress Tau (25). Collectively, these studies strongly suggest that an intermediate Tau aggregate preceding NFT formation may be responsible for neuronal dysfunction observed in AD and other tauopathies.…”

Section: Alzheimer Disease (Ad)mentioning

confidence: 74%

Characterization of Prefibrillar Tau Oligomers in Vitro and in Alzheimer Disease

Patterson

Remmers

et al. 2011

Journal of Biological Chemistry

301

354

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Neurofibrillary tangles, composed of insoluble aggregates of the microtubule-associated protein Tau, are a pathological hallmark of Alzheimer disease (AD) and other tauopathies. However, recent evidence indicates that neuronal dysfunction precedes the formation of these insoluble fibrillar deposits, suggesting that earlier prefibrillar Tau aggregates may be neurotoxic. To determine the composition of these aggregates, we have employed a photochemical cross-linking technique to examine intermolecular interactions of full-length Tau in vitro. Using this method, we demonstrate that dimerization is an early event in the Tau aggregation process and that these dimers selfassociate to form larger oligomeric aggregates. Moreover, using these stabilized Tau aggregates as immunogens, we generated a monoclonal antibody that selectively recognizes Tau dimers and higher order oligomeric aggregates but shows little reactivity to Tau filaments in vitro. Immunostaining indicates that these dimers/oligomers are markedly elevated in AD, appearing in early pathological inclusions such as neuropil threads and pretangle neurons as well as colocalizing with other early markers of Tau pathogenesis. Taken as a whole, the work presented herein demonstrates the existence of alternative Tau aggregates that precede formation of fibrillar Tau pathologies and raises the possibility that these hierarchical oligomeric forms of Tau may contribute to neurodegeneration.

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Section: Alzheimer Disease (Ad)mentioning

confidence: 74%

Characterization of Prefibrillar Tau Oligomers in Vitro and in Alzheimer Disease

Patterson

Remmers

et al. 2011

Journal of Biological Chemistry

301

354

View full text Add to dashboard Cite

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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: 79%

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.

177

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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“…Although plaques and tangles have traditionally been regarded as the main histopathological hallmarks of AD, a large body of evidence accumulated over the past decade suggests that soluble forms of these proteins are sufficient to trigger the development of the neurotoxicity process in AD (Berger et al., 2007; Bittner et al., 2010; Chabrier, Cheng, Castello, Green & LaFerla, 2014; Forner et al., 2017; Guerrero‐Munoz, Gerson & Castillo‐Carranza, 2015; Muller‐Schiffmann et al., 2016; Shankar et al., 2008; Spires‐Jones & Hyman, 2014; Tu, Okamoto, Lipton & Xu, 2014). These studies have clearly shown that soluble Aβ and tau oligomers are toxic to synapses and that the accumulation of these soluble isoforms correlates significantly with synaptic and memory impairments (Berger et al., 2007; Bittner et al., 2010; Chabrier et al., 2014; Forner et al., 2017; Guerrero‐Munoz et al., 2015; Muller‐Schiffmann et al., 2016; Shankar et al., 2008; Spires‐Jones & Hyman, 2014; Tu et al., 2014).…”

Section: Discussionmentioning

confidence: 99%

“…These studies have clearly shown that soluble Aβ and tau oligomers are toxic to synapses and that the accumulation of these soluble isoforms correlates significantly with synaptic and memory impairments (Berger et al., 2007; Bittner et al., 2010; Chabrier et al., 2014; Forner et al., 2017; Guerrero‐Munoz et al., 2015; Muller‐Schiffmann et al., 2016; Shankar et al., 2008; Spires‐Jones & Hyman, 2014; Tu et al., 2014). In addition, we have also demonstrated that Aβ oligomers modulate the development of tau pathology and accelerate cognitive and synaptic impairments (Chabrier et al., 2014).…”

Section: Discussionmentioning

confidence: 99%

Impaired AMPA signaling and cytoskeletal alterations induce early synaptic dysfunction in a mouse model of Alzheimer's disease

et al. 2018

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SummaryAlzheimer's disease (AD) is a devastating neurodegenerative disorder that impairs memory and causes cognitive and psychiatric deficits. New evidences indicate that AD is conceptualized as a disease of synaptic failure, although the molecular and cellular mechanisms underlying these defects remain to be elucidated. Determining the timing and nature of the early synaptic deficits is critical for understanding the progression of the disease and for identifying effective targets for therapeutic intervention. Using single‐synapse functional and morphological analyses, we find that AMPA signaling, which mediates fast glutamatergic synaptic transmission in the central nervous system (CNS), is compromised early in the disease course in an AD mouse model. The decline in AMPA signaling is associated with changes in actin cytoskeleton integrity, which alters the number and the structure of dendritic spines. AMPA dysfunction and spine alteration correlate with the presence of soluble but not insoluble Aβ and tau species. In particular, we demonstrate that these synaptic impairments can be mitigated by Aβ immunotherapy. Together, our data suggest that alterations in AMPA signaling and cytoskeletal processes occur early in AD. Most important, these deficits are prevented by Aβ immunotherapy, suggesting that existing therapies, if administered earlier, could confer functional benefits.

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Accumulation of Pathological Tau Species and Memory Loss in a Conditional Model of Tauopathy

Cited by 450 publications

References 43 publications

Characterization of Prefibrillar Tau Oligomers in Vitro and in Alzheimer Disease

Characterization of Prefibrillar Tau Oligomers in Vitro and in Alzheimer Disease

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

Impaired AMPA signaling and cytoskeletal alterations induce early synaptic dysfunction in a mouse model of Alzheimer's disease

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