Allosteric modulation of AMPA receptors counteracts Tau-related excitotoxic synaptic signaling and memory deficits in stress- and Aβ-evoked hippocampal pathology

Monteiro-Fernandes, Daniela; Silva, Joana M; Soares‐Cunha, Carina; Dalla, Christina; Kokras, Nikolaos; Arnaud, François; Billiras, Rodolphe; Zhuravleva, Viktoriya; Waites, Clarissa L.; Bretin, Sylvie; Sousa, Nuno; Sotiropoulos, Ioannis

doi:10.1038/s41380-020-0794-5

Cited by 14 publications

(8 citation statements)

References 69 publications

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“…However, impaired LTP is a well‐known component of AD pathology and reports have shown that selective enhancement of AMPAR signaling ameliorates stress‐induced cognitive deficits in mice injected i.c.v. with Aβ (Monteiro‐Fernandes et al., 2020). These opposing roles of glutamate in AD have not been fully reconciled in the literature, although involvement of extra‐synaptic NMDARs (the precise nature of which is debated) appears to be important (Zhou et al., 2013).…”

Section: Discussionmentioning

confidence: 99%

Lifelong chronic psychosocial stress induces a proteomic signature of Alzheimer's disease in wildtype mice

Lyons

Zhou

Razzoli

et al. 2021

Eur J of Neuroscience

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Late onset, sporadic Alzheimer's disease (AD) accounts for the vast majority of cases. Unlike familial AD, the factors that drive the onset of sporadic AD are poorly understood, although aging and stress play a role. The early onset/severity of neuropathology observed in most genetic mouse models of AD hampers the study of the role of aging and environmental factors; thus alternate strategies are necessary to understand the contributions of these factors to sporadic AD. We demonstrate that mice acquiring a low social status (subordinate) in a lifelong chronic psychosocial stress (CPS) model, accrue widespread proteomic changes in the frontal/temporal cortex during aging. To better understand the significance of these stress‐induced changes, we compared the differentially expressed proteins (DEPs) of subordinate mice to those of patients at varying stages of dementia. Sixteen and fifteen DEPs upregulated in subordinate mice were also upregulated in patients with mild cognitive impairment (MCI) and AD, respectively. Six of those upregulated proteins (CPE, ERC2, GRIN2B, SLC6A1, SYN1, WFS1) were shared by subordinate mice and patients with MCI or AD. Finally, comparison with a spatially detailed transcriptomic database revealed that the superior frontal gyrus and hippocampus had the greatest overlap between mice subjected to lifelong CPS and AD patients. Overall, most of the overlapping proteins were functionally associated with enhanced NMDA receptor mediated glutamatergic signaling, an excitotoxicity mechanism known to affect neurodegeneration. These findings support the association between stress and AD progression and provide valuable insight into potential early biomarkers and protein mediators of this relationship.

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Section: Discussionmentioning

confidence: 99%

Lifelong chronic psychosocial stress induces a proteomic signature of Alzheimer's disease in wildtype mice

Lyons

Zhou

Razzoli

et al. 2021

Eur J of Neuroscience

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“…It was proposed that modulating the balance between synaptic NR2A and extrasynaptic NR2B may improve behaviour ability in β-amyloid treated mice [ 77 ]. Tau involvement in excitotoxicity has been also described in AD [ 78 , 79 , 80 ] and FTD [ 81 ]. For a review of the role of glutamate receptors in AD, see in [ 82 ].…”

Section: Calcium Homeostasis Impairment In Ad and Tauopathiesmentioning

confidence: 99%

Mitochondrial Calcium Deregulation in the Mechanism of Beta-Amyloid and Tau Pathology

Esteras

Abramov

2020

Cells

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Aggregation and deposition of β-amyloid and/or tau protein are the key neuropathological features in neurodegenerative disorders such as Alzheimer’s disease (AD) and other tauopathies including frontotemporal dementia (FTD). The interaction between oxidative stress, mitochondrial dysfunction and the impairment of calcium ions (Ca2+) homeostasis induced by misfolded tau and β-amyloid plays an important role in the progressive neuronal loss occurring in specific areas of the brain. In addition to the control of bioenergetics and ROS production, mitochondria are fine regulators of the cytosolic Ca2+ homeostasis that induce vital signalling mechanisms in excitable cells such as neurons. Impairment in the mitochondrial Ca2+ uptake through the mitochondrial Ca2+ uniporter (MCU) or release through the Na+/Ca2+ exchanger may lead to mitochondrial Ca2+ overload and opening of the permeability transition pore inducing neuronal death. Recent evidence suggests an important role for these mechanisms as the underlying causes for neuronal death in β-amyloid and tau pathology. The present review will focus on the mechanisms that lead to cytosolic and especially mitochondrial Ca2+ disturbances occurring in AD and tau-induced FTD, and propose possible therapeutic interventions for these disorders.

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“…Tau is composed of two main domains: a projection domain (resides Met1-Tyr197) and an assembly domain (Ser198-Leu441). The first includes the N-terminal extension and the first part of a proline-rich region (residues 165–197), and the latter the second part of the proline-rich region, three or four microtubule binding repeats (MTBR, numbered R1 to R4) and a C-terminal extension [ 4 , 5 , 9 , 14 , 20 , 39 ].…”

Section: Taumentioning

confidence: 99%

“…Monteiro-Fernandes and colleagues proposed an intriguing therapeutic strategy to counteract tau-mediated excitotoxic synaptic and memory deficits in Aβ-dependent hippocampal pathology [ 39 ]. They chronically administered a positive allosteric modulator (PAM) of AMPAR to a non-transgenic mouse model of Aβ-oligomers.…”

Section: Taumentioning

confidence: 99%

NMDA and AMPA Receptors at Synapses: Novel Targets for Tau and α-Synuclein Proteinopathies

et al. 2022

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A prominent feature of neurodegenerative diseases is synaptic dysfunction and spine loss as early signs of neurodegeneration. In this context, accumulation of misfolded proteins has been identified as one of the most common causes driving synaptic toxicity at excitatory glutamatergic synapses. In particular, a great effort has been placed on dissecting the interplay between the toxic deposition of misfolded proteins and synaptic defects, looking for a possible causal relationship between them. Several studies have demonstrated that misfolded proteins could directly exert negative effects on synaptic compartments, altering either the function or the composition of pre- and post-synaptic receptors. In this review, we focused on the physiopathological role of tau and α-synuclein at the level of postsynaptic glutamate receptors. Tau is a microtubule-associated protein mainly expressed by central nervous system neurons where it exerts several physiological functions. In some cases, it undergoes aberrant post-translational modifications, including hyperphosphorylation, leading to loss of function and toxic aggregate formation. Similarly, aggregated species of the presynaptic protein α-synuclein play a key role in synucleinopathies, a group of neurological conditions that includes Parkinson’s disease. Here, we discussed how tau and α-synuclein target the postsynaptic compartment of excitatory synapses and, specifically, AMPA- and NMDA-type glutamate receptors. Notably, recent studies have reported their direct functional interactions with these receptors, which in turn could contribute to the impaired glutamatergic transmission observed in many neurodegenerative diseases.

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Allosteric modulation of AMPA receptors counteracts Tau-related excitotoxic synaptic signaling and memory deficits in stress- and Aβ-evoked hippocampal pathology

Cited by 14 publications

References 69 publications

Lifelong chronic psychosocial stress induces a proteomic signature of Alzheimer's disease in wildtype mice

Lifelong chronic psychosocial stress induces a proteomic signature of Alzheimer's disease in wildtype mice

Mitochondrial Calcium Deregulation in the Mechanism of Beta-Amyloid and Tau Pathology

NMDA and AMPA Receptors at Synapses: Novel Targets for Tau and α-Synuclein Proteinopathies

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