Biology subjects

Azoulay, B.

Publications and source records attributed to Azoulay, B..

3 recordsLinked to original sources

bioRxiv2025

AETA peptide drives Alzheimer's disease signature of synapse dysfunction

Alzheimers disease (AD), the leading cause of dementia, is characterized by early synaptic dysfunction that precedes overt cognitive decline. While amyloid-{beta} and Tau remain central to AD pathogenesis, molecular triggers of synapse weakening remain unclear. Here, we investigated AETA, a novel brain-secreted peptide derived from amyloid precursor protein (APP), as a potential mediator of synapse dysfunction in AD. We previously identified AETA as a unique modulator of NMDA receptor activity in the healthy brain; however, its role in AD etiology was yet to be explored. Post-mortem analyses of human hippocampal and prefrontal cortex tissues revealed significantly elevated AETA levels in AD patients, particularly in females. To further explore the contribution of AETA to AD synaptic pathology, we analyzed a new mouse model, the AETA-m mouse, exhibiting chronically increased brain AETA expression. Hippocampi of female AETA-m mice display an increase in the number of astrocyte and microglia, but no overt neuroinflammation. RNA sequencing of female AETA-m hippocampi revealed alterations in synaptic gene expression that closely paralleled those observed in vulnerable human AD brain regions, most notably in the hippocampus. These two phenotypes were absent in males. Functionally, hippocampal neurons from AETA-m mice displayed impaired NMDA receptor signaling, dendritic spine loss, and memory deficits especially in females, mirroring early AD-associated synaptic dysfunction. Together, these findings identify AETA as a novel key contributor of synaptic vulnerability in AD and associated memory processing, especially in females. Targeting AETA signaling may therefore offer new therapeutic avenues for preventing or mitigating synaptic and cognitive decline in AD.

neuroscience↗

bioRxiv2025

Cortico-striatal dynamics across working memory stages

Working memory depends on the temporary retention and manipulation of information, bridging the gap between short-term memory and information processing functions. However, when the same working memory task is repeated over several days, it raises the question of whether the rule or task set becomes automated (or proceduralized). The medial prefrontal cortex (mPFC) is crucial for working memory. Yet, the role of the dorsolateral striatum (DLS) in the automation (proceduralization) of rules or task sets remains to be clarified. Using a longitudinal approach of the "delay non-match to place" (DNMP) task in a T-maze combined to chemogenetic inhibition of the mPFC or DLS in mice, we show that the mPFC becomes less critical in the maintenance phase of the task as behaviour progressively shifts toward automation. During this phase, the DLS facilitates automated processing. Accordingly, silencing through chemogenetic inhibition of the DLS during maintenance triggers an adaptation in learning strategies, reactivating a goal-directed behaviour. Our findings strengthen memory traces as a dynamic reorganization of neural networks, challenging the classical view of information migration between brain structures. We here propose that the memory trace remains in a dormant state--less energy-consuming for the system--while still allowing for rapid flexibility in case of task modification.

neuroscience↗

bioRxiv2023

Iron regulatory proteins 1 and 2 have opposing roles in regulating inflammation in bacterial orchitis

Acute bacterial orchitis (AO) is a prevalent cause of intra-scrotal inflammation, often resulting in sub-or infertility. A frequent cause eliciting AO is uropathogenic Escherichia coli (UPEC), a gram negative pathovar, characterized by the expression of various iron acquisition systems to survive in a low-iron environment. On the host side, iron is tightly regulated by iron regulatory proteins (IRP) 1 and 2 and these factors have been reported to play a role in testicular and immune cell function, however, their precise role remains unclear. Here, we show in a mouse model of UPEC-induced orchitis that the absence of IRP1 results in reduced immune response and testicular damage. Compared to infected wild-type (WT)-mice, testis of UPEC-infected Irp1-/- mice showed impaired ERK signalling. Conversely, IRP2 deletion led to a stronger inflammatory response. Notably, differences in immune cell infiltrations were observed among the different genotypes. In contrast to WT and Irp2-/- mice, no increase in monocytes and neutrophils was detected in testis of Irp1-/- mice upon UPEC-infection. Interestingly, in Irp1-/- UPEC-infected testis, we observed an increase in a subpopulation of macrophages (F4/80+ CD206+) associated with anti-inflammatory and wound-healing activities compared to WT. These findings suggest that IRP1 deletion may protect against UPEC-induced inflammation by modulating ERK signalling and dampening the immune response.

immunology↗