Tau Diagnostics and Clinical Studies

Gozes, Illana; Höglinger, Günter U.; Quinn, James P.; Hooper, Nigel M.; Höglund, Kina

doi:10.1007/s12031-017-0983-0

Cited by 11 publications

(3 citation statements)

References 90 publications

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“…Our studies explain, in part, the efficacy of NAP (davuntide, CP201) in enhancing cognitive functions in mild cognitive impairment patients (18), while showing no efficacy (although high safety) in the 4R tauopathy progressive supranuclear palsy (PSP) (19). Since tauopathy underlies a verity of neurodegenerative conditions, our current findings may pave the path for treatment by peptide drugs that have an impact on tubulin-Tau interaction and specific neurofibrillary tangle populations (50). As neurodevelopment has been linked to Tau3R (7, 10), our results pave the path to the development of NAP (davunetide, CP201) for ADNP deficiencies associated with neurodevelopment, for example, the autism-like ADNP syndrome, resulting from de novo truncating mutations in ADNP (32).…”

Section: Discussionmentioning

confidence: 90%

NAP (davunetide) preferential interaction with dynamic 3-repeat Tau explains differential protection in selected tauopathies

Ivashko-Pachima

Maor

Gozes

2018

Preprint

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22The microtubule (MT) associated protein Tau is instrumental for the regulation of MT 23 assembly and dynamic instability, orchestrating MT-dependent cellular processes. 24 Aberration in Tau post-translational modifications ratio deviation of spliced Tau isoforms 25 3 or 4 MT binding repeats (3R/4R) have been implicated in neurodegenerative tauopathies. 26Activity-dependent neuroprotective protein (ADNP) is vital for brain formation and 27 cognitive function. ADNP deficiency in mice causes pathological Tau 28 hyperphosphorylation and aggregation, correlated with impaired cognitive functions. It has 29 been previously shown that the ADNP-derived peptide NAP protects against ADNP 30 deficiency, exhibiting neuroprotection, MT interaction and memory protection. NAP 31 prevents MT degradation by recruitment of Tau and end-binding proteins to MTs and 32 expression of these proteins is required for NAP activity. Clinically, NAP (davunetide, 33 CP201) exhibited efficacy in prodromal Alzheimer's disease patients (Tau3R/4R 34 tauopathy) but not in progressive supranuclear palsy (increased Tau4R tauopathy). Here, 35we examined the potential preferential interaction of NAP with 3R vs. 4R Tau, toward 36 personalized treatment of tauopathies. Affinity-chromatography showed that NAP 37 preferentially interacted with Tau3R protein from rat brain extracts and fluorescence 38 recovery after photobleaching assay indicated that NAP induced increased recruitment of 39 human Tau3R to MTs under zinc intoxication, in comparison to Tau4R. Furthermore, we 40 showed that NAP interaction with tubulin (MTs) was inhibited by obstruction of Tau-41 binding sites on MTs, confirming the requirement of Tau-MT interaction for NAP activity. 42The preferential interaction of NAP with Tau3R may explain clinical efficacy in mixed vs. 43Tau4R pathologies, and suggest effectiveness in Tau3R neurodevelopmental disorders. 44 45 Microtubules (MTs) are the major component of the neuronal cytoskeleton, and MT 46 stability and organization play a critical regulatory role during axonal transport and 47 synaptic transmission (1). The MT-associated protein Tau is widely expressed in neurons 48 and serves as a primary protein marker for axons (2, 3). Tau promotes MT assembly and 49 regulates MT dynamic instability, which is essential for establishing neuronal polarity, 50 axonal elongation, and neural outgrowth (4). Neurodegenerative disorders with Tau 51 involvement are referred to as tauopathies (5). The Tau protein consists of an N-terminus 52 region projecting outward from the MTs and a C-terminus part directly interacting with the 53 MTs through MT-binding domains (6). Tau3R and 4R (containing either three or four MT-54 tubulin -binding repeats, respectively) are produced by alternative splicing around exon 55 10 of the Tau transcript (7). The healthy human brain exhibits a 1/1 ratio of Tau3R/4R and 56 deviation from this ratio are the pathological feature of several tauopathies (8). 57Phosphorylation of Tau protein controls its binding to MT and is assoc...

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Section: Discussionmentioning

confidence: 90%

NAP (davunetide) preferential interaction with dynamic 3-repeat Tau explains differential protection in selected tauopathies

Ivashko-Pachima

Maor

Gozes

2018

Preprint

Self Cite

View full text Add to dashboard Cite

show abstract

“…Our studies explain, in part, the efficacy of NAP (davuntide, CP201) in enhancing cognitive functions in mild cognitive impairment patients [18], while showing no efficacy (although high safety) in the 4R tauopathy progressive supranuclear palsy (PSP) [19]. Since tauopathy underlies a verity of neurodegenerative conditions, our current findings may pave the path for treatment by peptide drugs that have an impact on tubulin-Tau interaction and specific neurofibrillary tangle populations [51]. As neurodevelopment has been linked to Tau3R [7, 10], our results pave the path to the development of NAP (davunetide, CP201) for ADNP deficiencies associated with neurodevelopment, for example, the autism-like ADNP syndrome, resulting from de novo truncating mutations in ADNP (32).…”

Section: Discussionmentioning

confidence: 97%

NAP (davunetide) preferential interaction with dynamic 3-repeat Tau explains differential protection in selected tauopathies

2019

Self Cite

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The microtubule (MT) associated protein Tau is instrumental for the regulation of MT assembly and dynamic instability, orchestrating MT-dependent cellular processes. Aberration in Tau post-translational modifications ratio deviation of spliced Tau isoforms 3 or 4 MT binding repeats (3R/4R) have been implicated in neurodegenerative tauopathies. Activity-dependent neuroprotective protein (ADNP) is vital for brain formation and cognitive function. ADNP deficiency in mice causes pathological Tau hyperphosphorylation and aggregation, correlated with impaired cognitive functions. It has been previously shown that the ADNP-derived peptide NAP protects against ADNP deficiency, exhibiting neuroprotection, MT interaction and memory protection. NAP prevents MT degradation by recruitment of Tau and end-binding proteins to MTs and expression of these proteins is required for NAP activity. Clinically, NAP (davunetide, CP201) exhibited efficacy in prodromal Alzheimer’s disease patients (Tau3R/4R tauopathy) but not in progressive supranuclear palsy (increased Tau4R tauopathy). Here, we examined the potential preferential interaction of NAP with 3R vs. 4R Tau, toward personalized treatment of tauopathies. Affinity-chromatography showed that NAP preferentially interacted with Tau3R protein from rat brain extracts and fluorescence recovery after photobleaching assay indicated that NAP induced increased recruitment of human Tau3R to MTs under zinc intoxication, in comparison to Tau4R. Furthermore, we showed that NAP interaction with tubulin (MTs) was inhibited by obstruction of Tau-binding sites on MTs, confirming the requirement of Tau-MT interaction for NAP activity. The preferential interaction of NAP with Tau3R may explain clinical efficacy in mixed vs. Tau4R pathologies, and suggest effectiveness in Tau3R neurodevelopmental disorders.

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“…AD involves a set of varying cognitive, functional, and behavioral dysfunctions resulting from neuropathological and biochemical changes in patients’ brains and may culminate in dramatic loss of autonomy (Schott & Warren, 2012). Its diagnosis is eminently clinical and entails a gradual and progressive neurodegenerative decline being translated into worse performance in cognitive tasks over time (Gozes, Höglinger, Quinn, Hooper, & Höglund, 2017). By and large, a progressive loss of memory is observed in AD; for recent events initially, as well as substantial difficulties in learning and decision making (Bondi, Edmonds, & Salmon, 2017).…”

Section: Dementia and Alzheimer’s Diseasementioning

confidence: 99%

New perspectives for cognitive rehabilitation: Could brain-computer interface systems benefit people with dementia?

Silva-Sauer¹,

Torre‐Luque²,

Silva³

et al. 2019

Psychology & Neuroscience

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This study aimed to discuss the usefulness of Brain-Computer Interface (BCI) systems as part of assistive technology strategies for cognitive rehabilitation and neuroplasticity promotion in people with dementia. A critical review was conducted. First, the essential principles of BCI systems were described. Electroencephalography-based systems, such as those based on either sensorial motor rhythms (SMRs) or event-related potentials (ERPs), are the focus of this review. Thus, some factors were identified to contribute to better understanding the foundations of brain-computer interaction within these systems. Moreover, we gathered and reviewed scientific evidence on the potential benefits of BCI-based rehabilitation strategies in people with dementia (e.g., Alzheimer’s disease). Existing evidence points to a relationship between SMR features and ERP signals with dementia diagnosis and its progression. In addition, BCI systems with contingent-reward neurofeedback were proven to generate significant modulations in some brain wave features promoting changes in cortical organization and connectivity. BCI devices constitute a promising tool for cognitive rehabilitation, leading to substantial benefits for patients across domains (e.g., attention, short-term memory [STM], or visuospatial orientation). Results from this review should promote the development of a noninvasive BCI system using a real-time neurofeedback to slow cognitive decline in people with dementia. However, further research with a robust methodology is needed to clarify the mechanisms underlying brain modulation facilitated by BCI systems, so as to develop BCI-based rehabilitation protocols for people with dementia.

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Tau Diagnostics and Clinical Studies

Cited by 11 publications

References 90 publications

NAP (davunetide) preferential interaction with dynamic 3-repeat Tau explains differential protection in selected tauopathies

NAP (davunetide) preferential interaction with dynamic 3-repeat Tau explains differential protection in selected tauopathies

NAP (davunetide) preferential interaction with dynamic 3-repeat Tau explains differential protection in selected tauopathies

New perspectives for cognitive rehabilitation: Could brain-computer interface systems benefit people with dementia?

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