LTP and memory impairment caused by extracellular Aβ and Tau oligomers is APP-dependent

Puzzo, Daniela; Piacentini, Roberto; Fà, Mauro; Gulisano, Walter; Puma, Domenica Donatella Li; Staniszewski, Agnes; Zhang, Hong; Tropea, Maria Rosaria; Cocco, Sara; Palmeri, Agostino; Fraser, Paul E.; D’Adamio, Luciano; Grassi, Claudio; Arancio, Ottavio

doi:10.7554/elife.26991

Cited by 137 publications

(132 citation statements)

References 65 publications

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“…9c, arrowheads over 3 th trace; from left to right) that were not present in presence of QX-314 alone (Fig. 9c, 4 Contrary to previously published data using extracellular Aβ or with more chronic application models [45][46][47][48][49][50], we did not find any synaptic deficits, instead, iAβo increased excitatory and inhibitory neurotransmissions, but with more marked effects on the former. This raises the question of how could iAβo actions progress to synaptic dysfunction in the first place?…”

Section: Iaβo Increased the Excitability Of Hippocampal Neurons In VIcontrasting

confidence: 90%

Functional spreading of hyperexcitability induced by human and synthetic intracellular Aβ oligomers

Fernández-Pérez

Muñoz

Bascuñán

et al. 2020

Preprint

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Background: Intracellular amyloid-beta oligomers (iAβo) accumulation and neuronal hyperexcitability are two crucial events at early stages of Alzheimer’s disease (AD). However, to date, no mechanism linking them has been reported. Methods: Here, the effects of human AD brain-derived (h-iAβo) and synthetic (iAβo) peptides on synaptic currents and action potential (AP) firing were investigated in hippocampal neurons in vitro , ex vivo and in vivo. Results: Starting from 500 pM, iAβo rapidly increased the frequency of synaptic currents and higher concentrations potentiated the AMPA receptor-mediated current. Both effects were PKC-dependent. Parallel recordings of synaptic currents and nitric oxide (NO)-related fluorescence changes indicated that the increased frequency, related to pre-synaptic release, was dependent on a NO-mediated retrograde signaling. Moreover, increased synchronization in NO production was also observed in neurons neighboring those dialyzed with iAβo, indicating that iAβo can increase network excitability at a distance. Current-clamp recordings suggested that iAβo increased neuronal excitability via AMPA-driven synaptic activity without altering membrane intrinsic properties. Conclusion: These results strongly indicate that iAβo causes functional spreading of hyperexcitability through a synaptic-driven mechanism and offer an important neuropathological significance to intracellular species in the initial stages of AD, which include brain hyperexcitability and seizures.

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Section: Iaβo Increased the Excitability Of Hippocampal Neurons In VIcontrasting

confidence: 90%

Functional spreading of hyperexcitability induced by human and synthetic intracellular Aβ oligomers

Fernández-Pérez

Muñoz

Bascuñán

et al. 2020

Preprint

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“…More recent data ascribed Tau oligomers as detrimental species towards plasticity. Interestingly, as Tau oligomers [178], Tau deletion also impairs hippocampal plasticity and spatial behavior [179-182]. This raises the possibility that both “toxic gain of Tau function” and “loss of normal Tau function” play a role in the development of cognitive deficits in tauopathies.…”

Section: Brain Insulin Resistance In Ad and Tauopathies: Cause Or Conmentioning

confidence: 99%

Mutual Relationship between Tau and Central Insulin Signalling: Consequences for AD and Tauopathies?

et al. 2018

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Alzheimer disease (AD) is a progressive neurodegenerative disorder mainly characterized by cognitive deficits and neuropathological changes such as Tau lesions and amyloid plaques, but also associated with non-cognitive symptomatology. Metabolic and neuroendocrine abnormalities, such as alterations in body weight, brain insulin impairments, and lower brain glucose metabolism, which often precede clinical diagnosis, have been extensively reported in AD patients. However, the origin of these symptoms and their relation to pathology and cognitive impairments remain misunderstood. Insulin is a hormone involved in the control of energy homeostasis both peripherally and centrally, and insulin-resistant state has been linked to increased risk of dementia. It is now well established that insulin resistance can exacerbate Tau lesions, mainly by disrupting the balance between Tau kinases and phosphatases. On the other hand, the emerging literature indicates that Tau protein can also modulate insulin signalling in the brain, thus creating a detrimental vicious circle. The following review will highlight our current understanding of the role of insulin in the brain and its relation to Tau protein in the context of AD and tauopathies. Considering that insulin signalling is prone to be pharmacologically targeted at multiple levels, it constitutes an appealing approach to improve both insulin brain sensitivity and mitigate brain pathology with expected positive outcome in terms of cognition.

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“…CREB is one of the pivotal transcription factors regulating the expression of various synaptic proteins. Studies show that extracellular application of tau oligomers or direct overexpression of tau or hyperphosphorylation and accumulation of tau by various molecules all reduced synaptic protein expression and disrupted glutamate receptor trafficking (Hoover et al, ; Puzzo et al, ; Vagnozzi, Giannopoulos, & Pratico, ). By overexpression hTau in primary hippocampal neurons, the decreased protein levels of BDNF, GluN1, GluN2A, GluA1, GluA2, PSD93, PSD95, and SYT were also detected with unchanged GluN2B, SYP, and SYN1.…”

Section: Discussionmentioning

confidence: 99%

Tau inhibits PKA by nuclear proteasome‐dependent PKAR2α elevation with suppressed CREB/GluA1 phosphorylation

Yin

Liu

et al. 2019

Aging Cell

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Intraneuronal accumulation of wild-type tau plays a key role in Alzheimer's disease, while the mechanisms underlying tauopathy and memory impairment remain unclear.Here, we report that overexpressing full-length wild-type human tau (hTau) in mouse hippocampus induces learning and memory deficits with remarkably reduced levels of multiple synapse-and memory-associated proteins. Overexpressing hTau inhib its the activity of protein kinase A (PKA) and decreases the phosphorylation level of cAMP-response element binding protein (CREB), GluA1, and TrkB with reduced BDNF mRNA and protein levels both in vitro and in vivo. Simultaneously, overex pressing hTau increased PKAR2α (an inhibitory subunit of PKA) in nuclear fraction and inactivated proteasome activity. With an increased association of PKAR2α with PA28γ (a nuclear proteasome activator), the formation of PA28γ-20S proteasome complex remarkably decreased in the nuclear fraction, followed by a reduced inter action of PKAR2α with 20S proteasome. Both downregulating PKAR2α by shRNA and upregulating proteasome by expressing PA28γ rescued hTau-induced PKA inhi bition and CREB dephosphorylation, and upregulating PKA improved hTau-induced cognitive deficits in mice. Together, these data reveal that intracellular tau accumula tion induces synapse and memory impairments by inhibiting PKA/CREB/BDNF/TrkB and PKA/GluA1 signaling, and deficit of PA28γ-20S proteasome complex formation contributes to PKAR2α elevation and PKA inhibition.

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LTP and memory impairment caused by extracellular Aβ and Tau oligomers is APP-dependent

Cited by 137 publications

References 65 publications

Functional spreading of hyperexcitability induced by human and synthetic intracellular Aβ oligomers

Functional spreading of hyperexcitability induced by human and synthetic intracellular Aβ oligomers

Mutual Relationship between Tau and Central Insulin Signalling: Consequences for AD and Tauopathies?

Tau inhibits PKA by nuclear proteasome‐dependent PKAR2α elevation with suppressed CREB/GluA1 phosphorylation

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