It is shown that Nav1.3, a subtype normally confined to early development, shows aberrantly increased expression in the dentate gyrus (DG)-CA3 circuit in early-stage 5xFAD mice, which is identified as a driver of early hippocampal network dysfunction in AD.
Alzheimer’s disease (AD) is characterized by progressive cognitive decline and stereotyped neuropathology, yet the earliest cellular events that precede overt plaque burden and measurable behavioral impairment remain incompletely defined. Here, we tested the hypothesis that synaptic hyperexcitability and subcellular metabolic dysfunction emerge early in the 5xFAD mouse model and contribute to region-specific neuronal vulnerability before substantial amyloid plaque deposition. Using the 5xFAD heterozygous mouse, we first established the onset of transgene expression and the timing of plaque accumulation. Robust transgene expression was detected by postnatal day 15 and statistically significant plaque accumulation in the CA1 stratum radiatum by 4 months of age. Hippocampal slice electrophysiology revealed an early hyperexcitable phenotype at 1 month of age, including both increased AMPA receptor-mediated transmission and N-methyl-D-aspartate receptor signaling associated with the GluN2B subunit. Given the tight coupling between glutamatergic hyperactivity, oxidative stress, calcium dysregulation, and mitochondrial health, we assessed mitochondrial structure and function at this pre-plaque stage. Mitochondrial abnormalities consistent with impaired bioenergetic homeostasis were evident within hippocampal synaptic processes. Morphological analyses demonstrated that these early changes were associated with altered dendritic architecture in the CA1 and dentate gyrus regions, revealing hippocampal subregional susceptibility. Finally, spatial transcriptomics identified regionally enriched molecular signatures consistent with differential vulnerability. The CA1 subregion exhibited pronounced downregulation of mitochondria-related transcripts, and single-cell deconvolution resolved this transcriptomic suppression specifically to CA1 pyramidal neurons (CA1.ProS); CA3 and dentate gyrus did not show equivalent mitochondrial pathway suppression. Together, these findings define a pre-plaque window in 5xFAD mice marked by GluN2B-linked glutamatergic hyperexcitability, early mitochondrial disruption, and selective dendritic and transcriptional vulnerability. Mitochondrial transcriptomic suppression was anatomically restricted to CA1 pyramidal neurons, establishing a cell-type-specific bioenergetic signature at 1 month of age, well before overt amyloid pathology. While the observations herein are descriptive in nature and detailed mechanisms have yet to be established, nevertheless, the integrated timeline suggests that synaptic and metabolic dysfunctions arise before substantial plaque deposition and may represent tractable early targets for intervention in AD.
Amanda R. Kelley, Emily Sackinger, M. Frischman et al.· Frontiers in Aging Neuroscie...· 0 citations
Results suggest that Adgrd1 plays a key role in maintaining hippocampal resilience and regulating motivational behaviors through integrated molecular and circuit-level mechanisms.
Inés Martínez-Soria, Pol Picón-Pagès, A. P. Pérez González et al.· bioRxiv· 0 citations
The entorhinal cortex (EC) plays a crucial role in memory functions. Long before the clinical symptoms of Alzheimer’s disease (AD) emerge, it has already undergone significant degeneration, making it a primary site for the onset of the disease. The reasons for this remain elusive. Layer II (LII) neurons of the anterolateral EC are especially prone to display a very early increase in intracellular amounts of amyloid-β peptide (Aβ) and hyperphosphorylated tau protein (p-tau). The expression of the large glycoprotein reelin is extraordinarily high in ECLII neurons compared to most other cortical neurons and proximity ligation assay data and other immunohistochemical data strongly support the notion that reelin binds to Aβ in these neurons. Here, based on the premise that reelin may function as a sink for intracellular Aβ, we show by computational modeling that, in a senescent physiology predisposing to frequent inflammation-driven Aβ42 production bursts over a decades-long period, the intracellular amount of Aβ42-reelin complexes can accumulate to extraordinarily high levels in anterolaterally positioned LII neurons compared to the vast majority of cortical neurons. This is consistent with experimental data showing that intracellular accumulations of Aβ42 positive material ranged from 20 to 80% of total soma volume in EC neurons from patients with idiopathic AD. Based on known tau protein biology, we also show that this extreme intracellular aggregation that overloads the lysosomal degradation machinery, manifesting chronic homeostatic dysregulation, can lead to the production of p-tau fragments prone to aggregation. Together, our findings may contribute to the resolution of why the EC is so strongly associated with the very early etiology of AD.
A. Kobro‐Flatmoen, J. Hussan, P. Hunter et al.· PLoS Computational Biology· 0 citations
To elucidate the early mechanisms underlying the long-term neuroprotective effect of FLASH-RT in the normal brain, spatial transcriptomics (Nanostring) were performed after whole-brain irradiation of C57BL/6J mice with either 1 or 3 fractions of 10 Gy at 5.6 × 106 Gy/s (1 pulse-FLASH) or at conventional dose-rate 0.1 Gy/s. FLASH-RT induced a distinct transcriptomic signature in the cornu ammonis region 3 (CA3) and dentate gyrus (DG) neurons, with upregulation of genes encoding glutamate receptors involved in calcium signaling, long-term potentiation, and mitochondrial OXPHOS. Early transcriptional upregulation of Gria genes translated into increased AMPAR protein levels at 48 h in the DG and CA3 region and sustained higher AMPAR expression at 2 and 4 weeks post-FLASH. These findings support a durable activation of AMPAR. We propose a mechanism to explain FLASH-induced neuroprotection initiated by early calcium influx and subsequent sustained expression of glutamate AMPARs in neurons and/or neural progenitors of the CA3, potentially contributing to long-term cognitive sparing.
Louis V. Kunz, A. Almeida, Michèle Knol et al.· Cell Reports· 0 citations
Alzheimer's disease (AD) is increasingly associated with early circuit dysfunction preceding cognitive decline, including neuronal hyperactivity and neuropsychiatric symptoms linked to mesolimbic pathways. The nucleus accumbens (NAc), a central regulator of reward and motivational processing, exhibits early alterations in excitation/inhibition balance in patients and experimental models, yet the synaptic mechanisms underlying its vulnerability remain unclear. Using a double transgenic APP/PS1 mice crossed with a Drd1a-tdTomato reporter line, we combined cell-type-specific electrophysiology, immunohistochemistry, ex vivo photometry, and behavioral assays. At a pre-plaque stage, intraneuronal Aβ accumulated in both dopamine D1 receptor-positive (D1R+) and D1R-negative medium spiny neurons (MSNs). Despite comparable Aβ levels, both high-frequency stimulation-induced long-term depression (LTD) and mGluR1/5-dependent LTD were selectively impaired in D1R+ MSNs. This vulnerability was accompanied by an increased contribution of calcium-permeable AMPA receptors (CP-AMPARs). Subsequent CP-AMPAR blockade reduced the residual evoked excitatory postsynaptic current that persisted after mGluR1/5 activation in APP/PS1 D1R+ MSNs. Because paired-pulse ratios remained unchanged, this residual response was consistent with a predominantly postsynaptic mechanism. These synaptic changes were accompanied by reduced evoked dopamine signaling, increased chocolate consumption, and altered baseline context preference, whereas standard pellet consumption, conditioned place preference, anxiety-like behavior, and social behavior were unchanged. These findings define a pre-plaque, cell-type-specific synaptic phenotype in male APP/PS1 mice in which impaired mGluR1/5-dependent plasticity and persistent CP-AMPAR signaling in D1R+ MSNs coincide with selective reward-related alterations.
Nicolás Riffo-Lepe, Juliana González-Sanmiguel, Isaías Meza et al.· Neurobiology of Disease· 0 citations
It is concluded that CA1 PCs hyperexcitability from Frm1 KO mice was detectable at late postnatal development (P21-28), but not earlier (P8-15), and was due to a shifting of action potential voltage threshold to more hyperpolarized values.
M. A. Luque, L. Dufresne, B. Torres et al.· Neuroscience· 0 citations
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