Alzheimer & Parkinson

Gastrointestinal dysfunction often precedes motor symptoms in Parkinson's disease (PD), suggesting the enteric nervous system (ENS) is central to early pathogenesis. How α-synuclein contributes to ENS dysfunction, and how inflammation modulates this, remains unclear. Here we show that Tumor Necrosis Factor alpha enhances α-synuclein accumulation in induced pluripotent stem cell-derived enteric neurons and glia, and impairs the malate-aspartate shuttle, a key pathway for mitochondrial energy...

Synucleinopathies is an umbrella term for multiple neurological disorders, including Parkinson's disease (PD), Lewy body dementia (LBD), and multiple system atrophy (MSA). A central pathological hallmark of synucleinopathies is the aggregation of α-synuclein (αS, a neuronal protein) and its prion-like spread. Therefore, inhibition of αS aggregation and spread is considered a viable therapeutic approach for the treatment of synucleinopathies. Foldamers are synthetic ligands that mimic the...

Memory-based cognition relies on the integrity of cortico-hippocampal circuits, which are compromised in Alzheimer's disease (AD) as β-amyloid (Aβ) and tau accumulate. However, the mechanisms linking this pathology to circuit dysfunction remain unclear. In mouse models, using in vivo two-photon and Neuropixels recordings, we show that Aβ-tau pathology promotes both region- and layer-specific impairments, involving reduced burst firing in superficial cortical layers and CA1 and reduced mean...

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Neurodegenerative diseases (NDs), including Alzheimer's disease (AD), Parkinson's disease (PD), dementia with Lewy bodies (DLB), and frontotemporal dementia (FTD), share overlapping clinical and pathological features. We analyzed cerebrospinal fluid (CSF) and plasma proteomes from 2,705 and 3,009 samples, respectively, across these NDs, identifying disease-specific and shared molecular signatures. CSF showed more disease-associated proteins than plasma, with AD and DLB exhibiting the strongest...

This study aims at implementing a 3D cell culture model of Alzheimer's disease (AD). To that end we engineered human induced pluripotent stem cell (iPSC)-derived neural stem cells to conditionally overexpress FAD mutant APP and PSEN1 variants. After differentiation in 3D basement membrane matrices, cultures exhibited increased Aβ(42) and Aβ(40) levels and a highly pathogenic shift of the Aβ(42/40) ratio. Typical AD phenotypes such as amyloid deposition and tau pathology were observed alongside...

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 dopamine neurons has...

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...

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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...