Alzheimer & Parkinson

Our understanding of Alzheimer's disease (AD) has transformed from a purely neuronal perspective to one that acknowledges the involvement of glial cells. Despite remarkable progress in unraveling the biology of microglia, astrocytes and vascular elements, the exploration of oligodendrocytes in AD is still in its early stages. Contrary to the traditional notion of oligodendrocytes as passive bystanders in AD pathology, emerging evidence indicates their active participation in and reaction to...

Glia contribute to the neuropathology of Parkinson disease (PD), but how they react opposingly to be beneficial or detrimental under pathological conditions, like promoting or eliminating SNCA/α-syn (synuclein alpha) inclusions, remains elusive. Here we present evidence that aux (auxilin), the Drosophila homolog of the PD risk factor GAK (cyclin G associated kinase), regulates the lysosomal degradation of SNCA/α-syn in glia. Lack of glial GAK/aux increases the lysosome number and size, regulates...

High-density lipoprotein (HDL) particle diameter distribution is informative in the diagnosis of many conditions, including Alzheimer's disease (AD). However, obtaining an accurate HDL size measurement is challenging. We demonstrated the utility of measuring the diameter of more than 1,800,000 HDL particles with the deep learning model YOLOv7 (you only look once) from micrographs of 183 HDL samples, including patients with dementia or normal cognition (controls). This method was shown to be more...

Parkinson's disease (PD) is the second most common central neurodegenerative disease in the world after Alzheimer's disease (AD), which mainly occurs in middle-aged and elderly people, and is increasing with the aging of the population. With the increasing incidence of PD, it is particularly important to explore its pathology and provide effective interventions and treatments. The pathogenesis of PD involves a variety of factors such as genetics, environment, and age, and is not yet fully...

Studies of the genetics of Alzheimer's disease (AD) have largely focused on single nucleotide variants and short insertions/deletions. However, most of the disease heritability has yet to be uncovered, suggesting that there is substantial genetic risk conferred by other forms of genetic variation. There are over one million short tandem repeats (STRs) in the genome, and their link to AD risk has not been assessed. As pathogenic expansions of STR cause over 30 neurologic diseases, it is important...

The ε4 variant of human apolipoprotein E (APOE4) is a key genetic risk factor for neurodegeneration in Alzheimer's disease and elevated all-cause mortality in humans. Understanding the factors and mechanisms that can mitigate the harmful effects of APOE4 has significant implications. In this study, we find that inactivating the VHL-1 (Von Hippel-Lindau) protein can suppress mortality, neural and behavioral pathologies caused by transgenic human APOE4 in Caenorhabditis elegans. The protective...

Mutations in Leucine-rich repeat kinase 2 (LRRK2) and PTEN-induced kinase 1 (PINK1) are associated with familial Parkinson's disease (PD). LRRK2 phosphorylates Rab guanosine triphosphatase (GTPases) within the Switch II domain while PINK1 directly phosphorylates Parkin and ubiquitin (Ub) and indirectly induces phosphorylation of a subset of Rab GTPases. Herein we have crossed LRRK2 [R1441C] mutant knock-in mice with PINK1 knock-out (KO) mice and report that loss of PINK1 does not impact...

Physical exercise is known to slow synaptic neurodegeneration and cognitive aging in Alzheimer's disease (AD). The benefits of physical exercise are related to reduced amyloid beta (Aβ) deposition and increased synaptic plasticity. Yet little is known about the mechanisms that mediate these effects. Here, we show that physical exercise down-regulated the microglial Tmem9 protein, inhibited C1q activation, and decreased C1q-dependent microglial synapse engulfment, eventually ameliorating...

Alternative splicing impacts most multi-exonic human genes. Inaccuracies during this process may have an important role in ageing and disease. Here, we investigate splicing accuracy using RNA-sequencing data from >14k control samples and 40 human body sites, focusing on split reads partially mapping to known transcripts in annotation. We show that splicing inaccuracies occur at different rates across introns and tissues and are affected by the abundance of core components of the spliceosome...

CONCLUSION: APOE4 may link PD and AD through shared genetic variants, inflammatory pathways, and dyslipidemia, involving both peripheral and central pathways. More comprehensive studies are required to ascertain the relationship between PD, AD, and APOE4, and to determine whether these associations are causal or non-causal in nature.

Alzheimer's disease (AD), an age-related neurodegenerative disease, brings huge damage to the society, to the whole family and even to the patient himself. However, until now, the etiological factor of AD is still unknown and there is no effective treatment for it. Massive deposition of amyloid-beta peptide(Aβ) and hyperphosphorylation of Tau proteins are acknowledged pathological features of AD. Recent studies have revealed that neuroinflammation plays a pivotal role in the pathology of AD....

An essential task in spatial transcriptomics is identifying spatially variable genes (SVGs). Here, we present Celina, a statistical method for systematically detecting cell type-specific SVGs (ct-SVGs)-a subset of SVGs exhibiting distinct spatial expression patterns within specific cell types. Celina utilizes a spatially varying coefficient model to accurately capture each gene's spatial expression pattern in relation to the distribution of cell types across tissue locations, ensuring effective...

Synaptic dysfunction is a primary hallmark of both Alzheimer's and Parkinson's disease, leading to cognitive and behavioral decline. While alpha-synuclein, beta-amyloid, and tau are involved in the physiological functioning of synapses, their pathological aggregation has been linked to synaptopathology. The methodology for studying the small-soluble protein aggregates formed by these proteins is limited. Here we describe SynPull, a method combining single-molecule pull-down, super-resolution...

Parkinson's disease (PD) is a prevalent neurodegenerative disorder characterized by pathological changes, including the loss of dopaminergic neurons and abnormal aggregation of α-synuclein (α-syn). Certain cellular and molecular events are involved; however, the origin and significance of these events remain uncertain. The discovery of microRNAs (miRNAs) predicted to play a pivotal role in various regulatory processes has emerged. Studies on the dysregulation of miRNAs in PD pathogenesis,...

Astrocytes help protect neurons from potential damage caused by reactive oxygen species (ROS). While ROS can also exert beneficial effects, it remains unknown how neuronal ROS signalling is activated during memory formation, and whether astrocytes play a role in this process. Here we discover an astrocyte-to-neuron H(2)O(2) signalling cascade in Drosophila that is essential for long-term memory formation. Stimulation of astrocytes by acetylcholine induces an increase in intracellular calcium...

The onset and development of Alzheimer's disease is linked to the accumulation of pathological aggregates formed from the normally monomeric amyloid-β peptide within the central nervous system. These Aβ aggregates are increasingly successfully targeted with clinical therapies at later stages of the disease, but the fundamental molecular steps in early stage disease that trigger the initial nucleation event leading to the conversion of monomeric Aβ peptide into pathological aggregates remain...

The pathogenesis of Lewy body diseases (LBDs), including Parkinson's disease (PD), involves α-synuclein (α-Syn) aggregation that originates in peripheral organs and spreads to the brain. PD incidence is increased in individuals with chronic renal failure, but the underlying mechanisms remain unknown. Here we observed α-Syn deposits in the kidneys of patients with LBDs and in the kidney and central nervous system of individuals with end-stage renal disease without documented LBDs. In male mice,...

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The basal ganglia (BG) play a key role in decision-making, preventing impulsive actions in some contexts while facilitating fast adaptations in others. The specific contributions of different BG structures to this nuanced behavior remain unclear, particularly under varying situations of noisy and conflicting information that necessitate ongoing adjustments in the balance between speed and accuracy. Theoretical accounts suggest that dynamic regulation of the amount of evidence required to commit...

In Alzheimer's disease (AD), amyloid-β (Aβ) triggers the aggregation and spreading of tau pathology, which drives neurodegeneration and cognitive decline. However, the pathophysiological link between Aβ and tau remains unclear, which hinders therapeutic efforts to attenuate Aβ-related tau accumulation. Aβ has been found to trigger neuronal hyperactivity and hyperconnectivity, and preclinical research has shown that tau spreads across connected neurons in an activity-dependent manner. Here, we...