1. Mol Psychiatry | Synaptic Vulnerability to β-Amyloid and Tau Pathologies Differentially Disrupts Emotional and Memory Neural Circuits
Research Background: The core symptoms of Alzheimer’s Disease (AD) include memory loss and neuropsychiatric abnormalities (such as anxiety), with pathological markers being amyloid beta (Aβ) plaques and tau neurofibrillary tangles in the brain. However, how Aβ and tau individually or synergistically disrupt specific neural circuits remains unclear.
Core Findings: Memory deficits are associated with tau pathology in the hippocampus (Tau and APP/Tau mice), while anxiety/fear behaviors are related to intracellular Aβ in the basolateral amygdala (BLA) (APP and APP/Tau mice); Aβ and tau synergistically impair hippocampal synaptic plasticity (LTP), but in the amygdala, they antagonize each other to mitigate LTP damage.
Mechanistic Analysis: Tau pathology directly disrupts synaptic connections in the hippocampus through synaptic tau accumulation, leading to memory impairment; Aβ pathology induces emotional abnormalities through intracellular deposition in the BLA, independent of synaptic tau; Tau mice primarily exhibit myelination and RNA processing abnormalities, while APP/Tau mice show inflammation and synaptic gene dysregulation; Aβ and tau jointly induce activation of astrocytes and microglia.
Scientific Significance: Interventional strategies targeting specific brain regions (hippocampus/amygdala) and pathological types (Aβ/tau) may be more effective, such as combined targeting of Aβ clearance and tau dephosphorylation therapies.
Methodological Highlights: Utilized three groups of transgenic mice (APP, Tau, and APP/Tau), transcriptome sequencing; comparisons at 6 months (early) and 9 months (late) reveal staged characteristics of pathological progression; focused on the hippocampus (memory center) and BLA (emotional center) to clarify region-specific pathological mechanisms.
2. Nat Neurosci | Retrieval of Conditional Immune Response in Male Mice is Mediated by Anterior-Posterior Insula Neural Circuit
Research Background: Conditional immune response (CIR) is a typical Pavlovian conditioned reflex. Although the insular cortex plays a key role in CIR, the specific neural circuit mechanisms remain unclear.
Core Findings: During the retrieval phase of CIR, the anterior insular cortex (AIC) → posterior insular cortex (PIC) neural pathway activation significantly increases; inhibiting the AIC → PIC pathway significantly reduces aversive behavior to the associated taste; bidirectional projections (AIC↔PIC) jointly regulate anticipatory immune responses; the immune response triggered by CIR recall (such as peritoneal macrophage activation) partially overlaps with results from direct LPS exposure but does not induce systemic cytokine (IL-6, MIP3α) elevation. After CIR retrieval, AIC→PIC neuron excitability decreases, with excitatory postsynaptic current (mEPSC) frequency and amplitude decreasing, while inhibitory postsynaptic current (mIPSC) frequency increases, leading to excitatory-inhibitory (E:I) imbalance.
Mechanistic Analysis: The AIC→PIC pathway primarily drives behavioral manifestations of CIR (such as aversion to saccharin), while immune responses (such as monocyte activation, CD80 expression upregulation) require bidirectional interaction between AIC and PIC; CIR retrieval leads to decreased synaptic efficacy of AIC→PIC neurons, possibly related to signal transmission inhibition due to E:I ratio imbalance.
Scientific Significance: Clarifying the roles of the AIC-PIC circuit in CIR provides a theoretical basis for developing immune therapies targeting specific neural circuits (such as modulating aversive behavior or excessive immune responses).
Methodological Highlights: Chemogenetics, electrophysiology.
Supplement
1. CIR Retrieval Phase
Definition: CIR refers to the immune response pattern established through classical conditioning. When an individual associates a neutral stimulus (such as a specific environment, sound, or smell) with an immune response during prior learning, this neutral stimulus becomes a conditioned stimulus. Upon encountering this conditioned stimulus again, the immune system reactivates the immune response associated with it, which is the retrieval phase of CIR.
Characteristics: The retrieval phase is the initial process of activating or recalling the immune response, involving the reactivation and response preparation of the immune system. During this phase, the immune system begins to recognize and respond to the conditioned stimulus, preparing for subsequent immune responses.
2. Post-Retrieval of CIR
Definition: Refers to the time point or phase after the conditional immune response has been activated or recalled. In this phase, the immune system has responded to the conditioned stimulus and may trigger a series of subsequent physiological or behavioral changes.
Characteristics: The post-retrieval phase marks the formal beginning of the immune response, which may involve activation of immune cells, release of inflammatory factors, and activation of the neuroendocrine system. These changes may further affect the individual’s physiological state (such as temperature, heart rate, etc.) and behavioral performance (such as emotions, pain perception, etc.).
3. Alzheimers Dement | CD83+ Microglia Associated with Alzheimer’s Disease Correlate with Increased Immunoglobulin G4 Levels in the Gut, Vagus Nerve, and Brain, and Presence of Human Cytomegalovirus
Research Background: Recent single-nucleus RNA sequencing (snRNAseq) studies have revealed a specific CD83+ microglia subtype in the brains of AD patients, which is associated with increased immunoglobulin G4 (IgG4) in the transverse colon (TC), but the specific mechanism remains unclear.
Core Findings: In AD patients, CD83+ microglia are significantly correlated with TC, superior frontal gyrus (SFG), and vagus nerve IgG4 and HCMV, and this association is validated in an independent AD cohort (universality); HCMV infection in human brain organoids accelerates the production of Aβ42 and pTau-212 (AD pathological markers) and induces neuronal death; in the cerebrospinal fluid (CSF) of CD83+ AD patients, IgG4 antibodies against HCMV antigens (such as UL99, UL13) significantly increase; HCMV infection induces CD83 expression in C20 microglia (a human microglia cell line).
Mechanistic Analysis: In Alzheimer’s disease patients, HCMV and host adaptive immune responses exhibit complex multi-tissue interactions through CD83+ microglia; this association may reflect the pathological physiological network between viral activation and neuroimmune responses.
Scientific Significance: Antiviral therapies targeting HCMV or IgG4 may become potential treatment strategies for AD, especially for patients carrying CD83+ microglia or HCMV biomarkers.
Methodological Highlights: Combined snRNAseq, RNA in situ hybridization (ISH), and brain organoid experiments; utilized serum epitope mapping analysis (SERA) based on random peptide libraries and proteomics-wide association studies (PIWAS) to identify specific targets of anti-HCMV IgG4 antibodies in CSF; replicated key findings in the ROSMAP independent AD cohort to enhance the reliability of results.
References:
1.Capilla-López MD, Deprada A, Andrade-Talavera Y, Martínez-Gallego I, Coatl-Cuaya H, Sotillo P, Rodríguez-Alvarez J, Rodríguez-Moreno A, Parra-Damas A, Saura CA. Synaptic vulnerability to amyloid-β and tau pathologies differentially disrupts emotional and memory neural circuits. Mol Psychiatry. 2025.
2.Kayyal H, Cruciani F, Chandran SK, Edry E, Schif-Zuck S, Koren T, Yiannakas A, Rolls A, Ariel A, Rosenblum K. Retrieval of conditioned immune response in male mice is mediated by an anterior-posterior insula circuit. Nat Neurosci. 2025; 28: 589-601.
3.Readhead BP, Mastroeni DF, Wang Q, Sierra MA, de Ávila C, Jimoh TO, Haure-Mirande JV, Atanasoff KE, Nolz J, Suazo C, Barton NJ, Orszulak AR, Chigas SM, et al. Alzheimer’s disease-associated CD83(+) microglia are linked with increased immunoglobulin G4 and human cytomegalovirus in the gut, vagal nerve, and brain. Alzheimers Dement. 2025; 21: e14401.
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