Alzheimer & Parkinson

Mitochondrial damage determines cell fate, leading to mitochondrial autophagy or cellular apoptosis in health and disease. The molecular mechanisms and role of the acto-myosin cytoskeleton regulating mitochondrial clearance and membrane remodeling are critical in neurodegenerative disease progression including Alzheimer, but remain unclear. To investigate the potential link between full-length Myosin VI (FL-Myo6) recruitment and exposure of the mitochondria-specific lipid cardiolipin (CL), here...

Imbalanced production and clearance of amyloid-β (Aβ) is a hallmark pathological feature of Alzheimer's disease (AD). While several monoclonal antibodies targeting Aβ have shown reductions in amyloid burden, their impact on cognitive function remains controversial, with the added risk of inflammatory side effects. Dysregulated stimulator of interferon genes (STING) signaling is implicated in neurodegenerative disorders, yet the biological interaction between this pathway and Aβ, as well as their...

The enzyme glucocerebrosidase (GCase) catalyses the hydrolysis of glucosylceramide to glucose and ceramide within lysosomes. Homozygous or compound heterozygous mutations in the GCase-encoding GBA1 gene cause the lysosomal storage disorder Gaucher disease, while heterozygous and homozygous mutations are the most frequent genetic risk factor for Parkinson's disease. These mutations commonly affect GCase stability, trafficking or activity. Here, we report the development and characterization of...

Polyamines are abundant and evolutionarily conserved metabolites that are essential for life. Dietary polyamine supplementation extends life-span and health-span. Dysregulation of polyamine homeostasis is linked to Parkinson's disease and cancer, driving interest in therapeutically targeting this pathway. However, measuring cellular polyamine levels, which vary across cell types and states, remains challenging. We introduce a genetically encoded polyamine reporter for real-time measurement of...

Sleep disturbances are associated with the pathogenesis of neurodegenerative diseases such as Alzheimer's disease and primary tauopathies. Here we demonstrate that administration of the dual orexin receptor antagonist lemborexant in the P301S/E4 mouse model of tauopathy improves tau-associated impairments in sleep-wake behavior. It also protects against chronic reactive microgliosis and brain atrophy in male P301S/E4 mice by preventing abnormal phosphorylation of tau. These neuroprotective...

Glymphatic function in animal models supports the clearance of brain proteins whose mis-aggregation is implicated in neurodegenerative conditions including Alzheimer's and Parkinson's disease. The measurement of glymphatic function in the human brain has been elusive due to invasive, bespoke and poorly time-resolved existing technologies. Here we describe a non-invasive multimodal device for the continuous measurement of sleep-active changes in parenchymal resistance in humans using repeated...

During infection, foreign DNA is sensed by cyclic GMP-AMP synthase (cGAS) leading to the production of cGAMP, STING-dependent type I interferon and proinflammatory cytokine expression, and autophagy. To prevent a response to self-DNA, cGAS activity is tightly regulated. Dysregulation of cGAS underpins interferonopathies, such as Aicardi-Goutières syndrome, as well as Lupus and neurodegenerative diseases like Parkinson's disease. Thus, cGAS and its product cGAMP are therapeutic targets. However,...

Microglia play a key role in the response to amyloid beta in Alzheimer's disease (AD). In this context, the major transcriptional response of microglia is the upregulation of APOE, the strongest late-onset AD risk gene. Of its three isoforms, APOE2 is thought to be protective, while APOE4 increases AD risk. We hypothesised that the isoforms change gene regulatory patterns that link back to biological function by shaping microglial transcriptomic and chromatin landscapes. We use RNA- and...

Genome-wide association studies (GWAS) on Alzheimer's disease (AD) have predominantly focused on identifying common variants in Europeans. Here, we performed whole-genome sequencing (WGS) of 1,559 individuals from a Korean AD cohort to identify various genetic variants and biomarkers associated with AD. Our GWAS analysis identified a previously unreported locus for common variants (APCDD1) associated with AD. Our WGS analysis was extended to explore the less-characterized genetic factors...

The activation of glycogen synthase kinase 3β (GSK-3β) and the deterioration of spatial memory represent prominent pathological and clinical manifestations of Alzheimer's disease (AD). Nevertheless, the precise intrinsic mechanisms linking these pathological features remain poorly elucidated. In this study, we identified significant upregulation of GSK-3β activity in inhibitory interneurons within the hippocampal dentate gyrus (DG) of 3×Tg-AD mice. Subsequent investigations demonstrated that...

Selective endoplasmic reticulum (ER) macroautophagy/autophagy, also called reticulophagy, is a disposal pathway that degrades ER domains. A major role of reticulophagy is the removal of ER domains that contain misfolded proteins resistant to ER-associated degradation (ERAD). Our studies have shown that RTN3L, the SEC24C-SEC23 COPII coat subcomplex, and the CUL3^(KLHL12) E3 ligase that ubiquitinates RTN3L targets ERAD-resistant misfolded protein condensates for degradation at ER-reticulophagy...

The silkworm Bombyx mori is an economically important insect for silk production. Its silk glands are responsible for the synthesis and secretion of silk proteins. The naked pupa (Nd), a fibroin heavy chain mutant strain of silkworm, was found to exhibit severe atrophy, degeneration of the posterior silk gland (PSG), and abnormal secretion of fibroin proteins, thereby producing little or no silk. Here, we found that the autophagic marker Atg8-PE was upregulated through the target of rapamycin...

Reactive gliosis is a hallmark of neuropathology and offers a potential target for addressing numerous neurological diseases. Here, we show that growth arrest and DNA damage inducible gamma (GADD45G), a stress sensor in astrocytes, is a nodal orchestrator of reactive gliosis and neurodegeneration. GADD45G expression in astrocytes is sufficient to incite astrogliosis, microgliosis, synapse loss, compromised animal behavior, and the aggravation of Alzheimer's disease (AD). Conversely, silencing...

CONCLUSIONS: Our results suggest that combining motor training with tDCS improves motor function, particularly in gait-related parameters, in PD patients. However, these effects were not sustained over time, highlighting the temporary nature of the benefits. Sex differences may influence the acute effects of combined motor training and tDCS interventions.

β-Site amyloid precursor protein (APP)-cleaving enzyme 1 (BACE1) is the rate-limiting enzyme for amyloid-β (Aβ) generation and is considered promising drug target for Alzheimer's disease (AD). The co-chaperone BAG3 (Bcl-2-associated athanogene 3) plays an important role in maintaining intracellular protein homeostasis by regulating heat shock protein 70 (HSP70). Here, we reported that BAG3 expression was significantly elevated in AD. It interacted with and stabilized BACE1 by delaying its...

Dysfunction of the glymphatic system, a brain-wide waste clearance network, is strongly linked to Alzheimer's disease (AD) and the accumulation of β-amyloid (Aβ) and tau proteins. Here, we identify an astrocytic signaling pathway that can be targeted to preserve glymphatic function and mitigate neurotoxic protein buildup. Analysis of astrocytes from both human AD brains and two transgenic mouse models (5XFAD and PS19) reveals robust activation of the protein kinase RNA-like endoplasmic reticulum...

The Miro1 protein is a member of the mitochondrial Rho GTPase (Miro) protein family and plays a crucial role in regulating the dynamic processes of mitochondria and participating in cellular movement and mitochondrial transport. In the nervous system, it ensures adequate energy supply for normal neuronal function and synaptic transmission. Additionally, Miro1 actively participates in the regulation of mitochondrial quality control and stress responses within neurons. Its primary function is to...

Alzheimer's disease (AD) is still an excessively complicated neurological disorder that impacts millions of individuals globally. The ideal defensive feature of the central nervous system (CNS) is the intimate junction of endothelial cells, which functions as a biological barrier to safely control molecular transport throughout the brain. The blood-brain barrier (BBB) comprises tightly locked astrocyte cell junctions on CNS blood capillaries. This biological barrier shields the brain from...

Tremor occurs in various forms across diverse neurological disorders, including Parkinson's disease and essential tremor. While clinically heterogeneous, converging evidence suggests a shared brain network may underlie tremor across conditions. Here, we empirically define such a network using four modalities: lesion locations, atrophy patterns, EMG-fMRI, and deep brain stimulation outcomes. We show that network connectivity robustly explains clinical outcomes in independent cohorts undergoing...

Preservation of synapses is crucial for healthy cognitive ageing, and synapse loss is one of the closest anatomical correlates of cognitive decline in Alzheimer disease, dementia with Lewy bodies and frontotemporal dementia. In these conditions, some synapses seem particularly vulnerable to degeneration whereas others are resilient and remain preserved. Evidence has highlighted that vulnerability and resilience are intrinsically distinct phenomena linked to specific brain structural and/or...