Luchena, C. | Search bioRxiv

bioRxiv2023

The nonlinear meccano of hyperactivity in Alzheimer

The pathophysiological process of Alzheimers disease (AD) is believed to begin many years before the formal diagnosis of AD dementia. This protracted preclinical phase offers a crucial window for potential therapeutic interventions, yet its comprehensive characterization remains elusive. Accumulating evidence suggests that amyloid-{beta} (A{beta}) may mediate neuronal hyperactivity in circuit dysfunction in the early stages of AD. At the same time, neural activity can also facilitate A{beta} accumulation through intricate feed-forward interactions, complicating elucidating the conditions governing A{beta}-dependent hyperactivity and its diagnostic utility. In this study, we use biophysical modeling to shed light on such conditions. Our analysis reveals that the inherently nonlinear nature of the underlying molecular interactions can give rise to various modes of hyperactivity emergence. This diversity in the mechanisms of hyperactivity may ultimately account for a spectrum of AD manifestations.

neuroscience↗

bioRxiv2021

A neuron, microglia, and astrocyte triple coculture model to study Alzheimer disease

Glial cells are essential to understand Alzheimers disease (AD) progression, given their role in neuroinflammation and neurodegeneration. There is a need for reliable and easy to manipulate models that allow studying the mechanisms behind neuron and glia communication. Currently available models such as cocultures require complex methodologies and/or might not be affordable for all laboratories. With this in mind, we aimed to establish a straightforward in vitro setting with neurons and glial cells to study AD. We generated a triple co-culture with neurons, microglia and astrocytes. Immunofluorescence, western blot and ELISA techniques were used to characterize the effects of oligomeric A{beta} (oA{beta}) in this model. We found that, in the triple co-culture, microglia increased the expression of anti-inflammatory markers Arginase I and TGF-{beta}1, and reduced pro-inflammatory iNOS and IL-1{beta}, compared with microglia alone. Astrocytes reduced expression of pro-inflammatory A1 markers AMIGO2 and C3, and displayed a ramified morphology resembling physiological conditions. Lastly, neurons increased post-synaptic markers, and developed more and longer branches than in individual primary cultures. Addition of oA{beta} in the triple coculture reduced synaptic markers and increased microglial activation, which are hallmarks of AD. Consequently, we developed a reliable model, where cells better resemble physiological conditions: microglia are less inflammatory, astrocytes are less reactive and neurons display a more mature morphology than in individual primary cultures. Moreover, we were able to recapitulate A{beta}-induced synaptic loss and inflammation. This model emerges as a powerful tool to study neurodegeneration and inflammation in the context of AD and other neurodegenerative diseases. Table of content image O_FIG_DISPLAY_L [Figure 1] M_FIG_DISPLAY C_FIG_DISPLAY Main pointsO_LIIn our model, microglia and astrocytes are less reactive, and neurons have a more mature morphology than in primary cultures. C_LIO_LIoA{beta} reduced synaptic markers and increased microglial activation. C_LIO_LIThis triple co-culture is a reliable tool to study neurodegeneration and gliosis in vitro. C_LI

neuroscience↗