Neuronal activity regulates extracellular tau in vivo

Yamada, Kaoru; Holth, Jerrah K.; Liao, Fan; Stewart, Floy R.; Mahan, Thomas E.; Jiang, Hong; Cirrito, John R.; Patel, Tirth K.; Hochgräfe, Katja; Mandelkow, Eva‐Maria; Holtzman, David M.

doi:10.1085/jgp.1434oia12

Cited by 58 publications

(85 citation statements)

References 17 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Numerous studies have linked AD-pathology and symptomology to disrupted functional coupling of cortical regions [85,86] resulting in cognitive dysfunction [23,87]. In support of the disconnection hypothesis, we found functional decoupling between the vmPFC and posterior parietal regions, which is further supported by the different network hierarchies we found in prodromal AD compared to SCD and HC.…”

Section: Disrupted Functional Coupling Of Prefrontal and Parietal Dmnsupporting

confidence: 85%

Functional Disintegration of the Default Mode Network in Prodromal Alzheimer’s Disease

Dillen¹,

Jacobs

Kukolja

et al. 2017

JAD

View full text Add to dashboard Cite

Abstract. Neurodegenerative brain changes can affect the functional connectivity strength between nodes of the default-mode network (DMN), which may underlie changes in cognitive performance. It remains unclear how the functional connectivity strength of DMN nodes differs from healthy to pathological aging and whether these changes are cognitively relevant. We used resting-state functional magnetic resonance imaging to investigate the functional connectivity strength across five DMN nodes in 25 healthy controls (HC), 28 subjective cognitive decline (SCD) participants, and 25 prodromal Alzheimer's disease (AD) patients. After identifying the ventral medial prefrontal cortex (vmPFC), posterior cingulate cortex (PCC), retrosplenial cortex (RSC), inferior parietal lobule, and the hippocampus we investigated the functional strength between DMN nodes using temporal network modeling. Functional coupling of the vmPFC and PCC in prodromal AD patients was disrupted. This vmPFC-PCC coupling correlated positively with memory performance in prodromal AD. Furthermore, the hippocampus decoupled from posterior DMN nodes in SCD and prodromal AD patients. There was no coupling between the hippocampus and the anterior DMN. Additional mediation analyses indicated that the RSC enables communication between the hippocampus and DMN regions in HC but none of the other two groups. These results suggest an anterior-posterior disconnection and a hippocampal de-coupling from posterior DMN nodes with disease progression. Hippocampal de-coupling already occurring in SCD may provide valuable information for the development of a functional biomarker.

show abstract

Section: Disrupted Functional Coupling Of Prefrontal and Parietal Dmnsupporting

confidence: 85%

Functional Disintegration of the Default Mode Network in Prodromal Alzheimer’s Disease

Dillen¹,

Jacobs

Kukolja

et al. 2017

JAD

View full text Add to dashboard Cite

show abstract

“…Reports that early Aβ deposition occurs preferentially in regions of high neuronal activity [170] and that secretion of Aβ is driven by synaptic activity [e.g., 171] suggests diffusion of extracellular glutamate to neighboring synapses could facilitate the spread of Aβ pathology. Similarly, recent work suggests presynaptic glutamate release is sufficient to drive tau release into the extracellular space [172]. Thus, glutamate-mediated exocytosis of tau may indicate one mechanism for the trans-synaptic spread of tau pathology associated with synaptic activity.…”

Section: Future Directionsmentioning

confidence: 92%

The Role of the Tripartite Glutamatergic Synapse in the Pathophysiology of Alzheimer’s Disease

Rudy¹,

Hunsberger²,

Weitzner³

et al. 2015

Aging and disease

138

106

View full text Add to dashboard Cite

Alzheimer's disease (AD) is the most common form of dementia in individuals over 65 years of age and is characterized by accumulation of beta-amyloid (Aβ) and tau. Both Aβ and tau alter synaptic plasticity, leading to synapse loss, neural network dysfunction, and eventually neuron loss. However, the exact mechanism by which these proteins cause neurodegeneration is still not clear. A growing body of evidence suggests perturbations in the glutamatergic tripartite synapse, comprised of a presynaptic terminal, a postsynaptic spine, and an astrocytic process, may underlie the pathogenic mechanisms of AD. Glutamate is the primary excitatory neurotransmitter in the brain and plays an important role in learning and memory, but alterations in glutamatergic signaling can lead to excitotoxicity. This review discusses the ways in which both beta-amyloid (Aβ) and tau act alone and in concert to perturb synaptic functioning of the tripartite synapse, including alterations in glutamate release, astrocytic uptake, and receptor signaling. Particular emphasis is given to the role of N-methyl-D-aspartate (NMDA) as a possible convergence point for Aβ and tau toxicity.

show abstract

“…Other studies have shown that release of Tau monomer is increased by synaptic activity (50,51). It remains unknown, however, whether trans-synaptic movement of aggregates is activity-dependent or whether it simply results from release of aggregated material at the axon terminal, where it is taken up by neighboring cells.…”

Section: Prion-like Propagation Of Protein Pathologymentioning

confidence: 99%

Prion-like Properties of Tau Protein: The Importance of Extracellular Tau as a Therapeutic Target

Holmes

Diamond

2014

Journal of Biological Chemistry

175

133

View full text Add to dashboard Cite

Work over the past 4 years indicates that multiple proteins associated with neurodegenerative diseases, especially Tau and ␣-synuclein, can propagate aggregates between cells in a prionlike manner. This means that once an aggregate is formed it can escape the cell of origin, contact a connected cell, enter the cell, and induce further aggregation via templated conformational change. The prion model predicts a key role for extracellular protein aggregates in mediating progression of disease. This suggests new therapeutic approaches based on blocking neuronal uptake of protein aggregates and promoting their clearance. This will likely include therapeutic antibodies or small molecules, both of which can be developed and optimized in vitro prior to preclinical studies.Neurodegenerative diseases account for an enormous human and financial cost to our society, estimated in excess of $200 billion annually (1). Despite decades of study, there is no disease-modifying therapy. Virtually all neurodegenerative diseases are associated with the accumulation of fibrillar protein aggregates, and all are relentlessly progressive. There is now abundant evidence for an association of neuronal networks with patterns of spread through the brain (2-4). Studies of relatively rare, dominantly inherited neurodegenerative diseases have indicated that proteins that accumulate in sporadic forms of disease, such as prion protein, Tau, ␣-synuclein, and TDP-43, also cause pathology in the setting of destabilizing point mutations (5-8). This provides a strong indication that protein aggregation is itself a proximal cause of disease and is not simply an epiphenomenon. Indeed, protein aggregation is the most unifying pathological feature of adult onset neurodegenerative disorders. The proximal initiators of protein aggregation likely vary among different proteins and cell types, whereas the accumulation of misfolded species in general appears to be linked to the age-dependent breakdown of cellular quality control pathways (9, 10). It is not understood, however, why neurodegenerative diseases are relentlessly progressive or why they involve neural networks (3,11,12). A variety of studies are consistent with the idea that mechanisms similar to those of propagation of prion pathology could underlie disease progression. Prion protein (PrP c ) 2 is a normal cellular protein that can be converted to a disease-causing conformation (PrP Sc ) through interaction with a pathogenic prion protein "seed." The conversion mechanism is not fully understood, but involves templated conformational change, whereby a PrP Sc seed contacts natively folded protein and induces it to assemble onto a growing aggregate. PrP Sc aggregates can have multiple conformations, each linked to unique pathological patterns (13-15), and they have been demonstrated in experimental systems to propagate through neural networks (16). Thus, the prion hypothesis provides a useful model by which to test ideas about propagation of protein pathology in other neurodegenerative diseases. Prion-...

show abstract

Neuronal activity regulates extracellular tau in vivo

Cited by 58 publications

References 17 publications

Functional Disintegration of the Default Mode Network in Prodromal Alzheimer’s Disease

Functional Disintegration of the Default Mode Network in Prodromal Alzheimer’s Disease

The Role of the Tripartite Glutamatergic Synapse in the Pathophysiology of Alzheimer’s Disease

Prion-like Properties of Tau Protein: The Importance of Extracellular Tau as a Therapeutic Target

Contact Info

Product

Resources

About