Alzheimer & Parkinson

Autophagosome closure by the endosomal sorting complex required for transport (ESCRT) complex is a prerequisite for their dynamin 2 (DNM2)-dependent release from the recycling endosome and subsequent lysosomal clearance. However, the mechanism that coordinates autophagosome closure and release is unknown. We identified that the Alzheimer's disease-associated protein bridging integrator 1 (BIN1) is a critical mediator of this coordination. Prior to autophagosome closure, BIN1 is held at...

The hyperpolarization-activated cyclic nucleotide-gated (HCN) channel is a voltage-gated cation channel that plays a crucial role in regulating cellular excitability, especially in cardiac pacemaker cells and neurons. Its dysregulation is linked to heart diseases such as bradycardia and neurological disorders such as epilepsy, Parkinson's disease, and neuropathic pain. Structural and functional studies have revealed that the S4 voltage sensor of the HCN channel moves downward during...

The vast microbial community residing in the gut is known as the gut microbiota (GM). Alterations in the compositional equilibrium of the GM, a phenomenon termed GM dysbiosis, have been increasingly associated with the pathogenesis of various diseases, particularly neuropsychiatric disorders. The microbiota-gut-brain axis (MGBA) serves as a bidirectional communication system that connects the gut to the brain. Notably, several prevalent neuropsychiatric disorders, including depression,...

Loss-of-function variants in the lipid transporter ABCA7 substantially increase the risk of Alzheimer's disease^(1,2), yet how they impact cellular states to drive disease remains unclear. Here, using single-nucleus RNA-sequencing analysis of human brain samples, we identified widespread gene expression changes across multiple neural cell types associated with rare ABCA7 loss-of-function variants. Excitatory neurons, which expressed the highest levels of ABCA7, showed disrupted lipid metabolism,...

Aging is a major risk factor for various neurological disorders, including Alzheimer's disease, and is associated with the accumulation of senescent cells, which can themselves propagate the senescence process through paracrine signaling. Migrasomes are organelles that form during cellular migration, detach from parent cells and mediate intercellular communication. Here we demonstrate that border-associated macrophages (BAMs) acquire senescence-associated properties during early brain aging,...

Clinical Alzheimer's disease is currently characterized by cerebral β-amyloidosis associated with cognitive impairment. However, most cases of Alzheimer's disease are associated with multiple neuropathologies at autopsy. The peripheral protein changes associated with these disease endophenotypes are poorly understood. In this study, we analyzed the plasma proteomes of individuals from four cohorts (n = 2,139 participants) to identify proteins and pathways associated with cerebral β-amyloidosis...

Subthalamic deep brain stimulation (STN-DBS) provides unprecedented spatiotemporal precision for the treatment of Parkinson's disease (PD), allowing for direct real-time state-specific adjustments. Inspired by findings from optogenetic stimulation in mice, we hypothesized that STN-DBS can mimic dopaminergic reinforcement of ongoing movement kinematics during stimulation. To investigate this hypothesis, we delivered DBS bursts during particularly fast and slow movements in 24 patients with PD....

The microglial surface protein Triggering Receptor Expressed on Myeloid Cells 2 (TREM2) plays a critical role in mediating brain homeostasis and inflammatory responses in Alzheimer's disease (AD). The soluble form of TREM2 (sTREM2) exhibits neuroprotective effects in AD, though the underlying mechanisms remain elusive. Moreover, differences in ligand binding between TREM2 and sTREM2, which have major implications for their roles in AD pathology, remain unexplained. To address these knowledge...

Evidence indicates that transposable elements (TEs) can contribute to the evolution of new traits, with some TEs acting as deleterious elements while others are repurposed for beneficial roles in evolution. In mammals, some KRAB-ZNF proteins can serve as a key defense mechanism to repress TEs, offering genomic protection. Notably, the family of KRAB-ZNF genes evolves rapidly and exhibits diverse expression patterns in primate brains, where some TEs, including autonomous LINE-1 and non-autonomous...

The Hippo signaling pathway is a key regulator of cell growth and cell survival, and hyperactivation of the Hippo pathway has been implicated in neurodegenerative diseases such as Huntington's disease. However, the role of Hippo signaling in Alzheimer's disease (AD) remains unclear. We observed that hyperactivation of Hippo signaling occurred in the AD model 5xFAD mice. To determine how inhibition of Hippo signaling might affect disease pathogenesis, we generated 5xFAD mice with conditional...

Engineering functional exosomes represents a cutting-edge approach in biomedicine, holding the promise to transform targeted therapy. However, challenges such as achieving consistent modification and scalability have limited their wider adoption. Herein, we introduce a universal and effective strategy for engineering multifunctional exosomes through cell fusion. The hybrid-cell-derived exosomes could combine the functional properties of both parental cells and be readily produced by passaging....

No abstract

Microglia regulate neuronal circuit plasticity. Disrupting their homeostatic function has detrimental effects on neuronal circuit health. Neuroinflammation contributes to the onset and progression of neurodegenerative diseases, including Alzheimer's disease (AD), with several microglial activation genes linked to increased risk for these conditions. Inflammatory microglia alter neuronal excitability, inducing metabolic strain. Interestingly, expression of APOE4, the strongest genetic risk factor...

Early and accurate Alzheimer's disease (AD) diagnosis is critical for effective intervention, but it is still challenging due to neurodegeneration's slow and complex progression. Recent studies in brain imaging analysis have highlighted the crucial roles of deep learning techniques in computer-assisted interventions for diagnosing brain diseases. In this study, we propose AlzFormer, a novel deep learning framework based on a space-time attention mechanism, for multiclass classification of AD,...

Achieving a deep understanding of brain mechanisms requires multi-scale perspectives to capture the architecture of complex networks. In this study, we focused on patients with cognitive impairment and constructed individual brain networks from neuroimaging data. We introduced a Significant Edges Selection (SES) method, which effectively extracts the most informative connections while suppressing noise. Using these refined features, we computed network characteristics and applied machine...

The distribution of tau pathology in Alzheimer's disease (AD) shows remarkable inter-individual heterogeneity, including hemispheric asymmetry. However, the factors driving this asymmetry remain poorly understood. Here we explore whether tau asymmetry is linked to i) reduced inter-hemispheric brain connectivity (potentially restricting tau spread), or ii) asymmetry in amyloid-beta (Aβ) distribution (indicating greater hemisphere-specific vulnerability to AD pathology). We include 452...

Parkinson's disease (PD) is characterized by the selective degeneration of midbrain dopaminergic neurons and aggregation of α-synuclein. Emerging evidence implicates the gut microbiome in PD, with microbial metabolites proposed as potential pathological mediators. However, the specific microbes and metabolites involved, and whether gut-derived metabolites can reach the brain to directly induce neurodegeneration, remain unclear. Here we show that elevated levels of Streptococcus mutans (S....

Aging is the main risk factor for Parkinson's disease (PD), yet our understanding of how age-related mechanisms contribute to PD pathophysiology remains limited. We conducted a longitudinal analysis of blood samples from the Parkinson's Progression Markers Initiative cohort to investigate DNA damage in PD. Patients with PD exhibited disrupted DNA repair pathways and biased suppression of longer transcripts, indicating age-related, transcription-stalling DNA damage. Notably, at the intake visit,...

Peroxisome proliferator-activated receptor (PPAR)-γ coactivator (PGC)-1α, interacts with numerous transcription factors implicated in a wide spectrum of biological responses. It has been identified as a key player in the transcriptional regulation of many mitochondrial components. The activity of PGC1-α is regulated at multiple levels, such as gene expression, transcriptional, post-transcriptional, and post-translational modification. The purpose of this review is to highlight the data...

Hydrogen sulfide (H(2)S) is an endogenously produced gasotransmitter that has garnered growing attention for its critical roles in cellular signalling and brain function. It regulates NMDA receptors during long-term potentiation, a fundamental mechanism underlying memory consolidation and influences neurotransmission and essential neurophysiological functions. H(2)S is synthesized by three enzymes: cystathionine γ-lyase (CSE) and cystathionine β-synthase (CBS) and 3-mercaptopyruvate...