Biology subjects

Melloni, A.

Publications and source records attributed to Melloni, A..

4 recordsLinked to original sources

bioRxiv2026

Lipidated ApoE is found in nanoscale proximity to Aβ aggregates in human Alzheimer brains.

Apolipoprotein E (APOE) associates with amyloid plaques (A{beta}) in Alzheimer disease (AD). The {varepsilon}4 allele of apolipoprotein E (APOE{varepsilon}4) is the strongest genetic risk factor for sporadic AD and exacerbates A{beta} plaque burden relative to APOE{varepsilon}3 and APOE{varepsilon}2. The majority of ApoE associates with multiple lipid classes to form lipoproteins both in the brain and the periphery. However, the lipidation status of A{beta} plaque-associated ApoE is not yet fully defined. Here, we use fluorescence lifetime imaging microscopy coupled with Forster resonance energy transfer (FLIM-FRET) to determine the lipidation status of ApoE in plaques, as well as the nanoscale spatial proximity of ApoE and A{beta} to anionic lipids and cholesterol within human AD brain tissue. We demonstrate that lipids are in close nanoscale proximity to ApoE and A{beta} within A{beta} plaques. Our results reveal that lipidated ApoE complexes enriched in anionic lipids and cholesterol are core constituents of AD plaques in-situ. We propose a pathological mechanism in which the surface presentation of anionic lipids on ApoE lipoproteins facilitates initial interaction with and subsequent aggregation of A{beta}.

neuroscience↗

bioRxiv2025

Rare bioactive tau oligomers from Alzheimer brain support both templated misfolding and fibril formation

In Alzheimers disease, both classical neurofibrillary tangles, and diffusible, aqueous soluble (High Molecular Weight, or HMW) species are able to support templated misfolding. How these tau proteoforms relate is uncertain. Using sequential size exclusion and anion exchange chromatography, we fractionated the HMW tau population and found both seed competent, and seed not competent proteoforms. Super resolution, atomic force, and immunogold electron microscopy confirmed that the size and conformation of both bioactive and non-bioactive tau proteoforms are similar, with dimers, trimers, and tetramers predominating. The presence of surface phosphorylation correlates with seeding capacity. Bioactive tau at fMol concentrations can induce seeding in a reporter cell. The soluble bioactive species support aggregation of a truncated repeat domain tau construct into thioflavin T positive fibrils and retain seeding activity over serial amplification in vitro and in cellulo, whereas non-bioactive oligomeric species do not. Together, these findings indicate that oligomeric assembly is required but not sufficient for seeding; instead, specific biochemical attributes of a rare oligomeric tau subset confer self-propagating, prion-like templated misfolding.

neuroscience↗

bioRxiv2025

Ubiquitin-Proteasome System Dysregulation in Alzheimer's Disease Impacts Protein Abundance

Alzheimers disease (AD) is a relentlessly progressive, fatal neurodegenerative disorder that results in widespread protein dysfunctions. However, the full extent of aberrant proteomic changes in AD and their impact remains unknown, in part, because of the challenges of comprehensively measuring the proteome. Here, we used plexDIA, an approach that provides deep proteomic coverage and high throughput by parallelizing the acquisition of peptides and samples, to characterize proteomic changes in AD. Using human dorsolateral prefrontal cortex tissue, we identified 281 differentially abundant proteins in AD. By systematically analyzing compartment and protein complex-specific shifts in protein abundance, we identified an AD-specific decrease in levels of the 20S proteasome, the catalytic core of the cells primary protein degradation pathway. This alteration was accompanied by widespread decreases in proteasome subunit stoichiometries. Many proteasome substrate proteins were negatively correlated with 20S levels and increased in AD, suggesting that reduced 20S levels leads to abnormal protein accumulation. By analyzing proteins increased in AD, we identify key properties of such proteins: They have fast degradation rates, they contain signal sequences that allow them to be targeted for proteasomal degradation, and they are targeted by quality control pathways that recognize mislocalized proteins. Changes in these gene products at the protein and mRNA levels were highly discordant, providing additional evidence for increased protein abundance driven by impaired clearance. We also identified coherent sets of ubiquitin system enzymes, proteins that target substrates for proteasomal degradation, whose levels robustly discriminate AD from non-AD samples. One subset exhibited consistent increases in AD, while another, which contained the tau E3 ligase Cul5, exhibited consistent decreases, revealing complex changes in the ubiquitin system in AD. Taken together, our results suggest that decreased ubiquitin-proteasome system capacity and impaired clearance of short-lived and mislocalized proteins contribute substantially to proteopathic burden in AD.

neuroscience↗

bioRxiv2023

APOE2 gene therapy reduces amyloid deposition, and improves markers of neuroinflammation and neurodegeneration in a mouse model of Alzheimer disease

Epidemiological studies show that individuals who carry the relatively uncommon APOE {varepsilon}2 allele rarely develop Alzheimer disease, and if they do they have a later age of onset, milder clinical course, and less severe neuropathological findings than others with Alzheimer disease. The contrast is especially stark in comparison to the phenotype associated with the major genetic risk factor for Alzheimer disease, APOE {varepsilon}4, which has an age of onset several decades earlier, as well as a more aggressive clinical course and notably more severe neuropathological findings, especially in terms of the amount of amyloid deposition. Even one APOE {varepsilon}2 allele improves phenotype, but it is uncertain if that is due to the replacement of a more toxic allele by APOE {varepsilon}2, or if APOE {varepsilon}2 has a protective, neuro-modulatory effect. Here, we demonstrate that brain exposure to APOE2 via a gene therapy approach which bathes the entire cortical mantle in the gene product after transduction of the ependyma, rapidly ameliorates established A{beta} plaque deposition, neurodegenerative synaptic loss, and, remarkably, reduces microglial activation in an APP/PS1 mouse model despite continued expression of human APOE4. This result suggests a promising protective effect of exogenous APOE2, revealing a cell non-autonomous effect of the protein on microglial activation. We also show that plaque associated microglia in the brain of patients who inherit APOE2 similarly have less microglial reactivity to plaques. These data raise the potential that an APOE2 therapeutic could be effective in Alzheimer disease even in individuals born with the risk {varepsilon}4 allele. One Sentence SummaryIntroduction of ApoE2 using an AAV that transduces the ependymal cells of the ventricle causes a reduction in amyloid load and plaque associated synapse loss, and reduces neuroinflammation by modulating microglial responsiveness to plaques.

neuroscience↗