Biology subjects

Wu, Y. C.

Publications and source records attributed to Wu, Y. C..

3 recordsLinked to original sources

bioRxiv2024

Human iPSC-derived pericyte-like cells carrying APP Swedish mutation overproduce beta-amyloid and induce cerebral amyloid angiopathy-like changes

Alzheimers disease (AD) patients often exhibit cerebral amyloid angiopathy (CAA), i.e beta-amyloid (A{beta}) accumulation within cerebral blood vessels causing cerebrovascular dysfunction. Pericytes wrap around vascular capillaries, thus regulating cerebral blood flow, angiogenesis, and vessel stability. Vascular dysfunction can promote the development and progression of neurodegenerative diseases, yet the specific contribution of pericytes to AD pathology remains unclear. Here we show that human induced pluripotent stem cell (iPSC)-derived pericyte-like cells (iPLCs) can generate A{beta} peptides, and that the cells carrying Swedish mutation in amyloid precursor protein (APPswe) secrete 10 times more A{beta}1-42 than the control cells. Additionally, APPswe iPLCs have an impaired capacity to support angiogenesis and barrier integrity, exhibit a prolonged contractile response, and produce increased levels of pro-inflammatory cytokines upon inflammatory stimulation. These functional alterations in APPswe iPLCs are accompanied by transcriptional upregulation of actin cytoskeleton and extracellular matrix organization-related genes. Therefore, the APPswe mutation in iPLCs recapitulates several features of CAA pathology in vitro. Our iPSC-based vascular cell model may thus serve as a platform for drug discovery targeting vascular dysfunction in AD.

cell biology↗

bioRxiv2022

Auditory cortical responses to speech are shaped by statistical learning of short-term speech input regularities

Speech perception presents an exemplary model of how neurobiological systems flexibly adjust when input departs from the norm. Dialects, accents, and even head colds can negatively impact comprehension by shifting speech from listeners expectations. Comprehension improves with exposure to shifted speech regularities, but there is no neurobiological model of this rapid learning. We used electroencephalography to examine human auditory cortical responses to utterances that varied only in fundamental frequency (F0, perceived as voice pitch) as we manipulated the statistical distributions of speech acoustics across listening contexts. Participants overtly categorized speech sampled across two acoustic dimensions that signal /b/ from /p/ (voice onset time [VOT] and F0) to model typical English speech regularities or an expectation-violating accent. These blocks were interleaved with passive exposure to two F0-distinguished test stimuli presented in an oddball ratio to elicit a cortical mismatch negativity (MMN) response. F0 robustly influenced speech categorization when short-term regularities aligned with English but F0 exerted no influence in the context of the accent. The short-term regularities modulated event-related potentials evoked by F0-distinguished test stimuli across both N1 and P3 temporal windows and, for P3 amplitude, there was a strong correlation with perceptual down-weighting of F0. The influence of the short-term regularities persisted to impact MMN in interleaved passive listening blocks when regularities mirrored English but were absent when regularities conveyed the accent. Thus, cortical response is modulated as a function of statistical regularities of the listening context, likely reflecting both early dimension encoding and later categorization. Significance StatementSpeech perception is a quintessential example of how neurobiological systems flexibly adjust when input departs from the norm. Perception is well-tuned to native-language speech patterns. Yet it adjusts when speech diverges from expectations, as with a foreign accent. We observe that the effectiveness of specific cues in speech, like the pitch of a voice, in signaling phonemes like /b/ versus /p/ is dynamically re-weighted when speech violates native-language expectations. We find that this re-weighting is mirrored in cortical responses that reflect both early acoustic dimension encoding and also in later responses linked to phoneme categorization. The results implicate dynamic adjustments in the mapping of speech to cortical representations, as modulated by statistical regularities experienced across local speech input.

neuroscience↗

bioRxiv2020

Patient iPSC-astrocytes show transcriptional and functional dysregulation in schizophrenia

Human astrocytes are multifunctional brain cells and may contribute to the pathophysiology of schizophrenia (SCZ). We differentiated astrocytes from induced pluripotent stem cells of monozygotic twins discordant for SCZ, and found sex-specific gene expression and signaling pathway alterations related particularly to inflammation and synaptic functions. While Ingenuity Pathway Analysis identified SCZ disease and synaptic transmission pathway changes in SCZ astrocytes, the most consistent findings were related to collagen and cell adhesion associated pathways. Neuronal responses to glutamate and GABA differed between astrocytes from control persons, affected twins, and their unaffected co-twins, and were normalized by clozapine treatment. SCZ astrocyte cell transplantation to the mouse forebrain caused gene expression changes in demyelination, synaptic dysfunction and inflammation pathways of mouse brain cells and resulted in behavioral changes in cognitive and olfactory functions. Altogether, our results show that astrocytes contribute to both familial risk and clinical manifestation of SCZ in a sex-specific manner.

neuroscience↗