Biology subjects

Saleki, S.

Publications and source records attributed to Saleki, S..

5 recordsLinked to original sources

bioRxiv2026

Mitochondrial dysfunction as a hallmark of brain senescence in telomerase-deficient mice

Neurodegenerative diseases, including Alzheimer's disease (AD), are strongly associated with aging. However, the molecular mechanisms underlying pathological brain aging remain incompletely understood. In this study, we used a mouse model of telomere attrition, a major driver of cellular senescence, to perform an unbiased analysis of how telomere-driven senescence affects cellular physiology and contributes to processes relevant to neurodegenerative conditions. After validating the presence of senescence hallmarks in telomerase-deficient brains, we characterized their transcriptomic and proteomic profiles. Mitochondrial function and associated energy metabolism emerged as the major dysregulated pathways, driven predominantly by proteomic rather than transcriptomic changes. Functional biochemical analyses on isolated brain mitochondria demonstrated impaired electron transport chain (ETC) complex activity and reduced energetic status, despite preserved ETC complex integrity and mitochondrial content. Further analyses in senescent primary neurons indicated an accumulation of dysfunctional mitochondria, characterized by increased reactive oxygen species (ROS) production and reduced ATP levels, although basal cellular respiration was maintained. At the tissue level, these alterations were associated with moderate reductions in neuronal density in the subiculum and cortical layer V, indicating region-specific vulnerability rather than widespread neurodegeneration. We propose that a major consequence of telomere dysfunction associated with pathological brain aging is the downregulation of mitochondrial activity, which contributes to the selective vulnerability of specific brain regions. These findings highlight mitochondrial pathways as attractive targets for interventions aimed at preserving brain health during aging.

neuroscience↗

bioRxiv2026

A modular neural circuit for computing the motion of objects

Computing the direction of a moving object requires integrating motion signals from its component edges into coherent patterns. The representation of pattern motion in visual cortex has been extensively studied, yet its underlying neural circuitry remains unknown. Using high-density recordings in macaque area MT, we show that selectivity to pattern motion emerges from a functionally and anatomically distinct cortical circuit. We demonstrate that neurons specialized for encoding component and pattern motion comprise distinct cell types arranged in a hierarchical circuit in which pattern neurons integrate inputs from a range of component neurons. Furthermore, we show that component and pattern neurons are spatially segregated into modules arranged systematically across cortical columns encoding direction of motion. This architecture and circuit align with a classic solution to the problem of computing the motion of objects.

neuroscience↗

bioRxiv2026

Alzheimer's disease-associated Presenilin 2 N141I mutation impairs neuronal lipid homeostasis and mitochondrial dynamics through selective downregulation of the Golgi exchange factor Gbf1

Presenilin 2 (PS2) mutations cause familial Alzheimers disease, yet their effects beyond amyloid processing remain poorly understood. Here, we investigated how PS2 deletion and the N141I mutation affect neuronal lipid homeostasis and mitochondrial dynamics in mouse primary neurons. Both PS2 deletion and N141I mutation reduced neuronal lipid content. However, exogenous lipid supplementation rescued this deficit only in N141I-expressing neurons, indicating a partial loss-of-function effect. N141I neurons also displayed reduced OPA1, a mitochondrial fusion regulator, restored by lipid supplementation. RNA-sequencing identified Gbf1, a Golgi-specific guanine nucleotide exchange factor, as selectively downregulated in N141I but not knockout tissue, which was confirmed at the protein level in mouse brain and primary neurons. Gbf1 knockdown in mouse embryonic fibroblasts (MEFs) recapitulated the N141I lipid profile. Together, these findings reveal a PS2-GBF1-lipid-mitochondria axis disrupted specifically by the N141I mutation, suggesting an amyloid-independent pathway contributing to neurodegeneration and identifying potential therapeutic targets for familial Alzheimers disease.

neuroscience↗

bioRxiv2022

Telomere-induced senescence increases aberrant intraneuronal amyloid-β accumulation by impairing autophagy in a mouse model of Alzheimer's disease

Aging is a well-known risk factor for Alzheimers disease (AD) and other neurodegenerative pathologies, but the molecular and cellular changes occurring in the aging brain are poorly understood. AD pathology seems to correlate with the appearance of cells that become senescent due to the progressive accumulation of cellular insults causing DNA damage. In this study, we investigated the role of cellular senescence on AD pathology by crossing an amyloid-{beta} (A{beta}) mouse model of AD (5xFAD) with a mouse model of senescence that is genetically deficient for the RNA component of the telomerase (Terc-/-). Our results show that accelerated senescence reduces amyloid plaque formation and A{beta} levels at an age when full-blown amyloid pathology is observed in 5xFAD mice. However, early and aberrant intraneuronal A{beta} accumulation is observed in the subiculum and cortical layer V of senescent mice. Selective neurodegeneration linked to telomere attrition and early intraneuronal A{beta} accumulation was observed in these particular regions. Finally, our results suggest that the effect of senescence on amyloid pathology might be mediated through an alteration in autophagy function. Altogether, these findings demonstrate the instrumental role of senescence in intraneuronal A{beta} accumulation associated to AD pathophysiology, and further support future approaches targeting these processes for therapeutic intervention.

neuroscience↗

bioRxiv2022

Exploring the frame effect

Probes flashed within a moving frame are dramatically displaced (Ozkan et al, 2021; Wong &Mack, 1981). The effect is much larger than that seen on static or moving probes (induced motion, Duncker, 1929; Wallach et al, 1978). These flashed probes are often perceived with the separation they have in frame coordinates -- a 100% effect. Here we explore this frame effect on flashed tests with several versions of the standard stimulus. We find that the frame effect holds for smoothly or abruptly displacing frames, even when the frame changed shape or orientation between the endpoints of its travel. The path could be non-linear, even circular. The effect was driven by perceived not physical motion. When there were competing overlapping frames, the effect was determined by which frame was attended. There were a number of constraints that limited the effect. A static anchor near the flashes suppressed the effect but an extended static texture did not. If the probes were continuous rather than flashed, the effect was abolished. The observational reports of 30 online participants suggest that the frame effect is robust to many variations in its shape and path and leads to a perception of flashed tests in their locations relative to the frame as if the frame were stationary. Our results highlight the role of frame continuity and of the grouping of the flashes with the frame in generating the frame effect.

neuroscience↗