Alzheimer & Parkinson

White matter hyperintensities (WMHs) are neuroimaging markers widely interpreted as caused by cerebral small vessel disease, yet emerging evidence suggests that a subset may have a neurodegenerative etiology. Current imaging methods have lacked the specificity to disentangle biological processes underlying WMHs in vivo. Here, we used voxel-level normative modeling and seven microstructural MRI markers with complementary biophysical sensitivities to generate single-subject high-resolution WMH...

Microglia play a major role in the pathophysiology of Parkinson's disease, where they regulate both α-synuclein (αSyn) aggregate clearance and inflammatory responses. Interferon gamma (IFNγ) is a strong immunomodulator, but its role in shaping human microglial phenotypes during αSyn exposure remains incompletely understood. Further, whether the secreted factors from microglia after exposure to αSyn pre-formed fibrils (PFFs) and IFNγ can affect morphology and functionality of dopaminergic neurons...

Multiple system atrophy (MSA) is a progressive neurologic disease, known as an α-synucleinopathy. There are currently no effective disease-modifying therapies for MSA. While neuroinflammation is a hallmark of MSA, the contribution of adaptive immune mechanisms remains poorly understood. Here, we profiled peripheral and central T cell responses in patients with MSA, in comparison with Parkinson's disease (PD) and healthy control cohorts, using single-cell transcriptomics, flow cytometry, and...

PINK1 is a master regulator of PINK1-parkin-mediated mitophagy, a key process for maintaining mitochondrial homeostasis. The precise regulation of PINK1 is therefore essential for orchestrating mitophagy. While proteolytic processing of PINK1 and degradation of cleaved PINK1 via the N-end rule under basal conditions have been extensively characterized, the mechanisms governing full-length PINK1 degradation upon mitochondrial damage remain enigmatic. Here, we demonstrate that PINK1 undergoes...

Lipid metabolism plays a crucial role in maintaining brain homeostasis, affecting energy balance, membrane structure, and signaling pathways essential for neuronal and glial health. Disruption of lipid pathways is linked to neuroinflammation and the progression of neurodegenerative diseases like Alzheimer's and Parkinson's, as well as aging. Changes in cholesterol trafficking, sphingolipid and ceramide metabolism, and phospholipid remodeling can compromise synaptic membrane integrity and...

APOE4 is the leading genetic risk factor for Alzheimer's disease, and chronic stress is a leading environmental risk factor. Studies suggest that APOE4 confers vulnerability to the behavioral and neuropathological effects of chronic stress, representing a potential mechanism by which this genetic variant accelerates Alzheimer's onset and progression. Whether and how APOE4-mediated stress vulnerability manifests in neurons of the hippocampus, a brain region particularly susceptible to stress and...

The G-protein-coupled receptor kinase 2 (GRK2) exerts essential functions in cell growth and survival. Searching for a connection between GRK2 and the neurodegenerative Alzheimer disease (AD), we find increased aggregated serine-670-phosphorylated GRK2 (phospho-S670-GRK2) in brains of AD mice and patients with dementia likely due to AD. Harmful phospho-S670-GRK2 aggregation is induced by two hallmark proteins of AD: beta-amyloid and the neurofibrillary-tangle-inducing, TAU-P301L. Aggregated...

Sex and apolipoprotein E ε4 (APOE4) interact to alter the risk for Alzheimer's disease and other neurodegenerative disorders. Herein, we show sex-specific differences in immune activation and lymphatic function in the meningeal dura of humanized female and male mice expressing two alleles of APOE4 (E4/E4), when compared with their respective sex-matched E3/E3 controls. We also describe distinct effects of APOE4 on brain lipid composition and inflammation in females and males that were partially...

Genetic variants affecting microglia can cause early-onset neurodegeneration or elevate Alzheimer's disease risk. To nominate regulators of relevant signaling pathways, we developed a genome-wide CRISPR screen in primary macrophages focused on survival. We identified Ptpn6, which encodes the inhibitory phosphatase SHP-1, as a crucial regulator for macrophage survival under reduced CSF1R signaling conditions in vitro. Deletion of Ptpn6 from adult microglia in vivo enhanced survival and decreased...

The stereochemical diversity of Aβ42 in the brains of patients with Alzheimer's disease (AD) is a clinically recognized but poorly understood phenomenon. A critical gap in our knowledge is how the complex mixture of these stereoisomers collectively influences the aggregation pathway and neurotoxicity of Aβ42 at the molecular level. Drawing from stereoproteome data from AD patient brain tissues and previous studies, we engineered a panel of stereoisomers to more simply simulate the stereochemical...

No abstract

Calcium signalling in astrocytes is a fundamental mechanism for maintaining brain homeostasis, shaping neuronal activity, and coordinating vascular and immune responses. Once considered secondary to neuronal signalling, astrocytic Ca^(2+) dynamics are now recognized as highly versatile, spatially compartmentalized and essential for regulating neurotransmitter uptake, ion buffering, metabolic support and mitochondrial function. Accumulating evidence shows that these Ca^(2+) signalling pathways...

Although systemic inflammation has been implicated in PD pathogenesis, the underlying mechanisms remain poorly understood. In this study, we investigate the pathological events in a systemic inflammation-induced PD mouse model. We demonstrate that synaptic loss in the midbrain occurs as early as 1 day after the final lipopolysaccharide (LPS) administration, preceding dopaminergic (DA) neuron degeneration, which was observed only at later stages (14 days). Early microglial activation in the...

Brain aging consists of a progressive loss of functional capacities, which is associated with a progressive cognitive decline and can lead to neurodegenerative diseases. Studies comparing the underlying molecular mechanisms of the human hippocampus between young and older adults remain scarce. In our study, we completed a transcriptomic analysis from hippocampal samples of different ages and performed 2 complementary analyses. A comparison between young and old groups revealed a set of genes...

Astrocytes regulate brain cholesterol homeostasis, but the astrocyte-specific mechanisms disrupted in Alzheimer's disease (AD) are poorly understood. By integrating human bulk transcriptomes with single-nucleus RNA sequencing (RNA-seq), we identified adipocyte enhancer-binding protein 1 (AEBP1) as an astrocyte-enriched factor upregulated in AD. In postmortem human tissue and 5×FAD mice, astrocytic AEBP1 levels rise with age and disease progression. Astrocyte-specific AEBP1 knockdown ameliorates,...

Transplantation-free neuron regeneration remains attractive yet unsolved for reversing Parkinson's disease (PD). Here, we present enzyme-driven mesoporous gold nanomotors (Apyrase@Au) that leverage endogenous biochemical energy for spatiotemporally controlled promotion of neural stem cell (NSC) differentiation, without exogenous stem cell transplantation. By catalyzing endogenous adenosine triphosphate (ATP) hydrolysis, Apyrase@Au nanomotors simultaneously generate directional propulsion and...

Interactions between amyloidogenic proteins are emerging as critical drivers of neurodegenerative diseases. Among others, in Alzheimer's disease (AD) and severe forms of chronic traumatic encephalopathy (CTE), codeposition of tau and amyloid-β (Aβ) leads to worsening of clinical outcomes and disease progression. Despite the importance of such heterotypic interactions, the underlying molecular mechanisms have proven challenging to be established. Here, we investigated the direct interaction...

Transcranial ultrasound stimulation (TUS) is an emerging method for non-invasive neuromodulation of deep brain structures. However, to date, there is no evidence that TUS can directly modulate disease-related pathological oscillations in the same direction as known therapies. Inspired by clinical deep brain stimulation, in this randomised controlled cross-over study we probed the effects of pallidal TUS pulsed at 130 Hz on subthalamic beta-band activity, a biomarker in Parkinson's Disease (PD)...

In early drug discovery, in vitro screening is frequently used, but selected candidates often fail in vivo. Induced pluripotent stem cell (iPSC)-based disease models offer improved physiological relevance; however, the high costs of media and differentiation procedures limit large-scale testing. Here, we develop a high-throughput conditioned-media-based screening system-the High-throughput screening technology for Aggregation Inhibitors of Diseased cell-derived Aggregative Proteins (HaiDap)...

LRRK2 (encoding leucine-rich repeat kinase 2) variants are the most common genetic cause of Parkinson's disease (PD). Lowering LRRK2 levels and/or inhibiting LRRK2 activity may modify PD-associated neuropathology. BIIB094 (ION859), an antisense oligonucleotide, targets LRRK2 mRNA for degradation. REASON was a first-in-human randomized phase 1 study investigating the safety, tolerability, pharmacokinetics and pharmacodynamics of intrathecal BIIB094 in patients with PD. In part A, 40 participants...