Translational Neurodegeneration最新文献

Background: Effective therapies for Alzheimer's disease (AD) remain to be developed. APOE4 is the strongest genetic risk factor for late-onset AD. Pericyte degeneration and blood-brain barrier (BBB) disruption are thought to be early biomarkers of AD and contribute to cognitive decline in APOE4 carriers, representing potential therapeutic targets. Our previous studies have shown that pericyte transplantation is one of the most effective strategies for BBB restoration, exhibiting great therapeutic potential for APOE4-related BBB damage and AD phenotypes.

Methods: APOE4/4 mice were treated with pericytes derived from APOE3/3 human induced pluripotent stem cells (hiPSCs). Behavioral tests, AD pathologies, and BBB integrity were assessed. Subsequently, temporal and spatial distribution of the transplanted pericytes was analyzed using tdTomato⁺ lentivirus labeling. Next, therapeutic effects of apoptotic vesicles (ApoVs) generated from APOE3/3 pericytes were evaluated in APOE4/4 pericytes in vitro. Additionally, transcriptomic and proteomic profiling were performed to identify key effector molecules in pericyte-derived ApoVs. Finally, the therapeutic effects of ApoVs derived from pericytes were evaluated in APOE4/4 mice.

Results: Early, multiple transplantations of pericytes derived from APOE3/3 hiPSCs robustly rescued cognitive decline and AD pathologies, restored BBB integrity, and prevented in situ pericyte degeneration in aged APOE4/4 mice. Intriguingly, ApoVs released from the infused cells, rather than the transplanted pericytes, were predominantly distributed in the brain, which were ingested by in situ APOE4/4 pericytes and then promoted functional recovery. We further characterized insulin growth factor-2 (IGF-2) as a key factor in APOE3/3 pericyte-derived ApoVs. Infusion of the in vitro generated ApoVs from APOE3/3 pericytes demonstrated distinct therapeutic effects in APOE4/4 mice, which were reversed by IGF2 knockout.

Conclusions: APOE3/3 pericytes or APOE3/3 pericyte-derived IGF2-rich ApoVs may offer promising therapeutic strategies for APOE4-associated AD.

Variants in the triggering receptor expressed on myeloid cells 2 (TREM2) gene have been demonstrated to increase the risk of late-onset Alzheimer's disease (AD) and Nasu-Hakola disease. As a type I transmembrane receptor, TREM2 is predominantly expressed in microglia within the central nervous system. Extensive research over the past decade has consistently established the critical role of TREM2 in AD pathogenesis, encompassing its regulation of microglial inflammatory responses, amyloid-β deposition, and tau pathology. Notably, the soluble TREM2 fragment (sTREM2) is emerging as a promising candidate biomarker for clinical progression of AD, as evidenced by human studies. Despite these advances, the precise roles of membrane-bound TREM2 and sTREM2 in AD pathogenesis remain incompletely elucidated. Novel mouse models and technological innovations have enabled therapeutic approaches targeting TREM2 for neuroprotection. This review summarizes this progress and highlights areas for future research towards the development of TREM2-directed therapeutics.

Background: Defective autophagic flux is implicated in Alzheimer's disease (AD), but the molecular mechanisms underlying this process are not fully understood. Salt-inducible kinase 2 (SIK2) is associated with autophagic function. However, its specific involvement in autophagic flux regulation and AD pathogenesis remains unclear.

Methods: We evaluated hippocampal SIK2 expression and its age-related changes in postmortem AD patients and 5 × FAD mice by bioinformatics analysis, immunofluorescence, qPCR, and Western blotting. To investigate the functional role of SIK2, we employed adeno-associated virus-mediated SIK2 knockdown and overexpression in combination with behavioral tests (Morris water maze), electrophysiological recordings (long-term potentiation, LTP), and ultrastructural analysis (electron microscopy) to evaluate cognitive function and synaptic plasticity. Autophagic flux was measured using LC3B/p62 turnover assays, mRFP-GFP-LC3 tandem fluorescence assay, and transmission electron microscopy. Mechanistic insights were gained through co-immunoprecipitation assay, GST-pull down assay, phosphoproteomics, and site-directed mutagenesis. Additionally, phosphorylation-mimetic (S72E) and non-phosphorylatable (S72A) mutants of GABA type A receptor-associated protein-like 2 (GABARAPL2) were intrahippocampally delivered to 5 × FAD mice to explore their effects.

Results: Our study identified SIK2 as a critical regulator that is progressively downregulated in hippocampal neurons of AD patients and 5 × FAD mice, correlating with spatial memory deficits. Reducing SIK2 levels exacerbates cognitive impairment and amyloid-β (Aβ) plaque burden in mice, whereas restoring SIK2 levels mitigates these deficits, restores LTP amplitude, reverses synaptic ultrastructural pathology, and reduces Aβ deposition. Mechanistically, SIK2 enhances autophagic flux by phosphorylating GABARAPL2 at Ser72, a modification essential for autophagosome-lysosome fusion. Remarkably, hippocampal delivery of the phosphorylation-mimetic GABARAPL2-S72E mutant replicated the beneficial effects of SIK2, alleviating Aβ pathology and synaptic dysfunction in 5 × FAD mice. In contrast, the non-phosphorylatable S72A mutant failed to show any protective effects.

Conclusions: These findings establish the SIK2-GABARAPL2 axis as a novel signaling cascade governing autophagic flux through lysosomal fusion competence. Dysfunction in this axis contributes to Aβ deposition in AD, offering new insights into the pathogenic mechanisms underlying autophagosome-lysosome fusion in AD and highlighting its potential as a therapeutic target.

Neurodegenerative disorders, notably Alzheimer's and Parkinson's diseases, are unified by progressive neuronal loss and aberrant protein aggregation. Growing evidence indicates that these conditions are linked to cancer, infectious diseases, and type 2 diabetes through convergent molecular processes. In this review, we examine the mechanistic foundations of these links, focusing on shared features such as protein misfolding and aggregation, chronic inflammation, and dysregulated signalling pathways. We integrate cellular, animal, and human data to illustrate how pathogenic proteins may influence one another through cross-seeding and co-aggregation, and assess the implications of such interactions for disease susceptibility, progression, and treatment response. Understanding these underlying mechanisms may provide a conceptual framework for developing therapeutic approaches that target the molecular basis of multiple complex disorders.

Alzheimer's disease (AD) is one of the most common and devastating neurodegenerative diseases, characterized by accumulation of amyloid-beta (Aβ) plaques, neurofibrillary tangles of tau protein, and persistence of neuroinflammation, leading to progressive cognitive decline, loss of independence, emotional and financial strain on families, and significant societal costs. Current anti-amyloid treatments are partly successful in removing Aβ amyloid, but often lead to increased inflammation. This leads to limited therapeutic efficacy and causes side effects such as amyloid-related imaging abnormalities. In addition, they do not address neuroinflammation in AD patients. In this review, we discuss a new therapeutic strategy that combines single-domain antibodies (sdAbs, nanobodies) against Aβ fibrils and anti-inflammatory drugs and applies them to the regions of neuroinflammation associated with the plaques in AD patients. This strategy aims to control the function of activated microglia and astrocytes, thereby avoiding unnecessary immunosuppression. We also discuss the unique features of sdAbs, including small size, good tissue penetration, and lack of Fc-mediated immune reactions, as well as relevant payloads (i.e., small molecules, biologics, and nanoparticles) and delivery systems. This immunomodulatory therapy targets the plaques specifically and therefore represents a promising opportunity to improve amyloid clearance and target the inflammatory components of AD, potentially improving the therapeutic efficacy of the disease.

Hippocampus (HPC)-associated spatial memory deficits are one of the earliest symptoms of Alzheimer's disease (AD). Current pharmacological treatments only alleviate the symptoms but do not prevent disease progression. The emergence of neuromodulation technology suggests that specific neural circuits are potential therapeutic targets for AD. Current studies have analyzed the medial septum (MS)-HPC and the HPC-lateral septum (LS) circuitries separately. A comprehensive understanding of their synergistic effects and overall dysregulation in AD remains limited. In this review, we will integrate anatomical and functional evidence to give an overview of the role of the MS-HPC-LS circuitry in spatial memory, the mechanisms of AD-related dysregulation, and therapeutic strategies targeting the circuitry, specially focusing on molecular interventions (receptor modulation) and bioengineering strategies (circuit-specific stimulation).

Background: Alzheimer's disease (AD) is characterized by accumulation of amyloid-β (Aβ) plaques, tau neurofibrillary Tangles and synaptic dysfunction. The aim of this study was to map the distributions of synaptic vesicle protein 2A (SV2A) and other synaptic proteins in the brain and the brain-derived extracellular vesicles (BDEVs) of AD patients, analyze their associations with Aβ, tau, and the apolipoprotein E (APOE) ε4 allele, and investigate the biological role of SV2A.

Methods: Mass spectrometry-based proteomics of BDEVs and immunohistochemistry staining were conducted on postmortem brain samples from 57 AD patients and 48 nondemented controls. The levels of SV2A, synaptophysin (SYP), and other synaptic proteins in the brain tissues and the BDEVs, and their associations with Aβ, tau (phospho-tau and Braak stages), other proteins and the APOE ε4 allele, were analyzed.

Results: SV2A levels were significantly lower in AD patients than in nondemented controls, particularly in the hippocampus and entorhinal cortex. APOE ε4 carriers presented further reductions in SV2A levels compared with noncarriers. The SV2A levels in BDEVs and brain tissues were positively correlated with SYP levels and negatively correlated with Aβ and phospho-tau levels. Reductions in SV2A were associated with decreased levels of other synaptic proteins, such as synaptotagmins, GAP43, and SNAP25. SV2A emerged as a central hub with interactions with proteins from subnetworks related to synaptic vesicle formation and fusion.

Conclusion: SV2A levels in brain tissues and BDEVs are reduced in AD patients, particularly in those carrying the APOE ε4 allele, and are correlated with Aβ and tau pathologies. SV2A may serve as a valuable biomarker for monitoring synaptic dysfunction and progression in AD.

The glymphatic system serves as the brain's clearance system. It deteriorates with age and is a significant contributor to the onset and progression of Alzheimer's disease (AD). Modulating cerebrospinal fluid (CSF)-based clearance and targeting key components of the glymphatic system, such as aquaporin-4, can enhance amyloid-beta (Aβ) clearance. Light therapy is emerging as a potential AD treatment approach, which involves the use of visible and near-infrared light at specific wavelengths (630/680/808/850/1070 nm), photosensitive proteins, and sensory stimulation at particular frequencies (e.g., 40 Hz). This phototherapy strategy can broadly influence the intracerebral fluid dynamics, including cerebral blood flow, CSF, and interstitial fluid (ISF), as well as structures related to the glymphatic system, such as vascular endothelial cells, glial cells, and neurons. Additionally, it may directly or indirectly inhibit Aβ accumulation by modulating endogenous small molecules, thereby improving cognitive function. Our previous research demonstrated that 630-nm red light can inhibit Aβ cross-linking by clearing endogenous formaldehyde and promoting ISF drainage. Notably, Aβ accumulation exhibits distinct characteristics at different phases of AD, accompanied by varying features of glymphatic system impairment. In the early stages, deep brain regions are significantly affected, whereas in the late stages, accumulation primarily occurs in the paracentral, precentral, and postcentral cortices. Owing to the limited penetration depth of light, this may pose a challenge to the clinical efficacy of phototherapy. Therefore, different stages of AD may require tailored phototherapeutic strategies. Meanwhile, it is important to acknowledge the ongoing controversies associated with lymphovenous anastomosis, a procedure that targets the glymphatic system. Therefore, this article reviews the characteristics of glymphatic system impairment across various AD stages and the mechanisms by which effective phototherapies modulate the glymphatic system. Potential phototherapeutic strategies corresponding to different stages of Aβ accumulation are also proposed.