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Alzheimer's disease pathology degrades an NMDA receptor-dependent spontaneous activity pattern in cortico-hippocampal circuits

1 month 3 weeks ago
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...
Robert Ellingford

Large-scale CSF and plasma proteomics reveal immune, synaptic, and extracellular matrix disruptions across neurodegenerative diseases

1 month 3 weeks ago
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...
Muhammad Ali

Recapitulation of plaque formation, tau pathology, and neurodegeneration in a human 3D matrix model of Alzheimer's disease

1 month 3 weeks ago
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...
Matthias Hebisch

Characterizing spatiotemporal white matter hyperintensity pathophysiology in vivo to disentangle vascular and neurodegenerative contributions

1 month 3 weeks ago
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...
Olivier Parent