bioRxiv Subject Collection: Neuroscience's Journal

Direct disassembly of alpha-syn preformed fibrils into native alpha-syn monomers by an all-D-peptide
Parkinson's disease (PD) is the most common neurodegenerative movement disorder worldwide. One of its central features is the neurodegeneration that starts in the substantia nigra and progressively tends to involve other brain regions. Alpha-Synuclein (alpha-syn) and its aggregation during pathogenesis have been drawn into the center of attention, where especially soluble oligomeric and fibrillar structures are thought to play a key role in cell-to-cell transmission and induction of toxic effects. Here, we report the development of all-D-enantiomeric peptide ligands that bind monomeric alpha-syn with high affinity, thereby stabilizing the physiological intrinsically disordered structure and preventing initiation of aggregation, and more important, disassembling already existing aggregates. This "anti prionic" mode of action (MoA) has the advantage over other MoAs that it eliminates the particles responsible for disease propagation directly and independently of the immune system, thereby restoring the physiological monomer. Based on mirror image phage display on the D-enantiomeric full-length alpha syn target, we identified SVD-1 and SVD-1a by next generation sequencing, Thioflavin-T screens and rational design. The compounds were analyzed with regard to their anti-aggregation potential and both compounds showed aggregation delaying as well as seed capacity reducing effects in de novo and seeded environments, respectively. High affinity towards the monomeric alpha-syn, in the low nano- to picomolar KD range was identified by surface plasmon resonance (SPR). SVD-1a reduced toxic effects as well as intracellular seeding capacity of alpha-syn pre-fromed fibrils (PFF) in cell culture. SVD-1a disassembled -syn PFF into monomers as identified by atomic force microscopy (AFM), time dependent dynamic light scattering (DLS) and size exclusion chromatography (SEC) analysis. The present work provides promising results on the development of lead compounds with this anti-prionic mode of action for treatment of Parkinson's disease and other synucleinopathies.

Geometric-relationship specific transfer in visual perceptual learning
Visual perceptual learning (VPL) is defined as long-term improvement on a visual task as a result of visual experience. In many cases, the improvement is highly specific to the location where the target is presented, which refers to location specificity. In the current study, we investigated the effect of a geometrical relationship between the trained location and an untrained location on transfer of VPL. We found that significant transfer occurs either diagonally or along a line passing the fixation point. This indicates that whether location specificity or location transfer occurs at least partially depends on the geometrical relationship between trained location and an untrained location.

'Pscore' - A Novel Percentile-Based Metric to Accurately Assess Individual Deviations in Non-Gaussian Distributions of Quantitative MRI Metrics
BACKGROUND: Quantitative MRI metrics could be used in personalized medicine to assess individuals against normative distributions. However, conventional Zscore analysis is inadequate for measurements with non-Gaussian distributions. PURPOSE or HYPOTHESIS: Demonstrate systematic skewness in diffusion MRI (dMRI) metrics. Propose a novel percentile-based method, 'Pscore' to address this and document its performance on a publicly available dataset. STUDY TYPE Cohort: POPULATION 961 healthy young adults, the Human Connectome Project (HCP) FIELDSTRENGTH/SEQUENCE Siemens 3T 'Connectome Skyra' scanner, spin-echo diffusion echo planar imaging (EPI) ASSESSMENT The dMRI data was preprocessed using the TORTOISE pipeline. Average values within 48 regions of interest (ROIs) were computed from various diffusion tensor (DT) and mean apparent propagator (MAP) metrics. For each ROI, percentile ranks across participants were first computed to generate 'Pscores'- which normalize the difference between the median and a participant's value with the corresponding difference between the median and the 5th/95th percentile values. STATISTICAL TESTS ROIwise distributions were assessed using 'Log'-transformation, 'Zscore' and the 'Pscore' methods. The distributions and percentages of extreme values (>95th and <5th percentile boundaries) were also compared across all ROIs comprising the overall white matter. Bootstrapping was performed to test the reliability of Pscores in small samples (N=100) using 100 iterations. RESULTS: The dMRI metrics demonstrated systematic skewness, leading to skewed 'Log'-transform and 'Zscore' distributions. Zscores showed extreme value biases, which were strongest for the Propagator Anisotropy. 'Pscore' distributions were symmetric and robustly maintained 5% extreme values in both tails, even for 100 iterations in small, bootstrapped samples. DATA CONCLUSION: The inherent skewness observed for dMRI metrics preclude the use of conventional Zscore analysis. The proposed 'Pscore' method accurately estimates individual deviations in skewed normative data. Although the HCP dMRI data was showcased, Pscores offer a general solution, even for smaller databases with non-Gaussian distributed values of neuroimaging and clinical measurements. Keywords: Normative Distribution, Individual Deviations, Skewness, Diffusion MRI, Zscores, Extreme Value Bias

Atenolol reduces cardiac-mediated mortality in a genetic mouse model of sudden unexpected death in epilepsy
Sudden Unexpected Death in Epilepsy (SUDEP) is the leading cause of premature mortality in epilepsy. Genetic cardiac risk factors, including loss-of-function KCNH2 variants, have been linked to SUDEP. We hypothesised that seizures and LQTS interact to increase SUDEP risk. To investigate this, we crossed Kcnh2+/- and Gabrg2R43Q/+ mice that model LQTS and genetic epilepsy, respectively. Electrocorticography and electrocardiogram confirmed that Kcnh2+/- mice had a LQTS phenotype, while Gabrg2R43Q/+ mice displayed spontaneous seizures. Double mutant mice (Kcnh2+/-/Gabrg2R43Q/+) had both seizure and LQTS phenotypes that were indistinguishable from the respective single mutant mice. Survival analysis revealed that Kcnh2+/-/Gabrg2R43Q/+ mice experienced a disproportionate higher rate of seizure-related death. Long-term oral administration of atenolol, a cardiac-selective {beta}-blocker, significantly improved survival in the Kcnh2+/-/Gabrg2R43Q/+ mice. Overall, the data implicates loss-of-function KCNH2 variants as an important risk factor, and the potential repurposing of beta-blockers as a prevention strategy, for SUDEP in a subset of epilepsy patients.

Functional Connectivity, Tissue Microstructure And T2 At 11.1 Tesla Distinguishes Neuroadaptive Differences In Two Contusive Brain Injury Models In Rats
The damage caused by contusive traumatic brain injuries (TBIs) is thought to involve breakdown in neuronal communication through focal and diffuse axonal injury along with alterations to the neuronal chemical environment, which adversely affects neuronal networks beyond the injury epicenter(s). In the present study, functional connectivity along with brain tissue microstructure coupled with T2 relaxometry were assessed in two experimental TBI models in rat, controlled cortical impact (CCI) and lateral fluid percussive injury (LFPI). Rats were scanned on an 11.1 Tesla scanner on days 2 and 30 following either CCI or LFPI. Naive controls were scanned once and used as a baseline comparison for both TBI groups. Scanning included functional magnetic resonance imaging (fMRI), diffusion weighted images (DWI), and multi-echo T2 images. fMRI scans were analyzed for functional connectivity across laterally and medially located region of interests (ROIs) across the cortical mantle, hippocampus, and dorsal striatum. DWI scans were processed to generate maps of fractional anisotropy, mean, axial, and radial diffusivities (FA, MD, AD, RD). The analyses focused on cortical and white matter (WM) regions at or near the TBI epicenter. Our results indicate that rats exposed to CCI and LFPI had significantly increased contralateral intra-cortical connectivity at 2 days post-injury. This was observed across similar areas of the cortex in both groups. The increased contralateral connectivity was still observed by day 30 in CCI, but not LFPI rats. Although both CCI and LFPI had changes in WM and cortical FA and diffusivities, WM changes were most predominant in CCI and cortical changes in LFPI. Our results provide support for the use of multimodal MR imaging for different types of contusive and skull-penetrating injury.

Tuning of cortical color mechanism revealed using steady-state visually evoked potentials
Color information is thought to be received by the primary visual cortex via two dominant retinogeniculate pathways, one signals color variation between teal and red, and the other signals color variation between violet and lime. This representation is thought to be transformed in the cortex so that there are a number of different cell populations representing a greater variety of hues. However, the properties of cortical color mechanisms are not well understood. In four experiments, we characterized the tuning functions of cortical color mechanisms by measuring the intermodulation of steady-state visually evoked potentials (SSVEPs). Stimuli were isoluminant chromatic checkerboards where odd and even checks flickered at different frequencies. As hue dissimilarity between the odd and even checks increased, the amplitude of an intermodulation component (I1) at the sum of the two stimulus frequencies decreased, revealing cortical color tuning functions. In Experiment 1 we found similar broad tuning functions for 'cardinal' and intermediate color axes, implying that the cortex has intermediately tuned color mechanisms. In Experiment 2 we found similar broad tuning functions for 'checkerboards' with no perceptible edges because the checks were formed from single pixels (~0.096{degrees}), implying that the underlying neural populations do not rely on spatial chromatic edges. In Experiment 3 we manipulated check size and found that color tuning functions were consistent across check sizes used. In Experiment 4 we measured full 360{degrees} tuning functions for a cardinal cortical color mechanism and found evidence for opponent (bipolar) color responses. The observed cortical color tuning functions were consistent with those measured using psychophysics and electrophysiology, implying that tracking intermodulation using SSVEPs provides a useful method for measuring them.

Uncovering network mechanism underlying thalamic Deep Brain Stimulation using a novel firing rate model
Thalamic ventral intermediate nucleus (Vim) is the primary surgical target of deep brain stimulation (DBS) for reducing symptoms of essential tremor. In-vivo single unit recordings of patients with essential tremor revealed that low frequency Vim-DBS ([≤]50Hz) induces periodic excitatory responses and high-frequency Vim-DBS ([≥]100Hz) induces a transient excitatory response lasting for [≤]600ms followed by a suppressed steady-state. Yet, the neural mechanisms that generate Vim firing rate in response to different DBS frequencies are not fully uncovered. Previously developed models of Vim neurons could not capture the full dynamics of Vim-DBS despite incorporating the dynamics of short-term synaptic plasticity. In this work, we developed a network rate model and a novel parameter optimization method to accurately track the instantaneous firing rate of Vim neurons in response to various DBS frequencies, ranging in low- and high-frequency (5 to 200Hz) Vim-DBS. We showed that the firing rate dynamics during high frequency Vim-DBS are best characterized when incorporating an inhibitory population into the network model. Further, we discovered that the Vim firing rate in response to varying frequencies of DBS pulses can be explained by a balanced amplification mechanism, in which strong excitation (Vim) is stabilized by equally strong feedback inhibition. As a further validation of this work, we demonstrated similar behavior in a detailed biophysical model consisting of spiking neural networks in which the Vim neural-network can implement balanced amplification and explain in-vivo human Vim-DBS observations.

Evolutionary and Developmental Specialization of Foveal Cell Types in the Marmoset
In primates, high-acuity vision is mediated by the fovea, a small specialized central region of the retina. The fovea, unique to the anthropoid lineage among mammals, undergoes notable neuronal morphological changes during postnatal maturation. However, the extent of cellular similarity across anthropoid foveas and the molecular underpinnings of foveal maturation remain unclear. Here, we used high throughput single cell RNA sequencing to profile retinal cells of the common marmoset (Callithrix jacchus), an early divergent in anthropoid evolution from humans, apes, and macaques. We generated atlases of the marmoset fovea and peripheral retina for both neonates and adults. Our comparative analysis revealed that marmosets share almost all its foveal types with both humans and macaques, highlighting a conserved cellular structure among primate foveas. Furthermore, by tracing the developmental trajectory of cell types in the foveal and peripheral retina, we found distinct maturation paths for each. In-depth analysis of gene expression differences demonstrated that cone photoreceptors and Muller glia, among others, show the greatest molecular divergence between these two regions. Utilizing single-cell ATAC-seq and gene-regulatory network inference, we uncovered distinct transcriptional regulations differentiating foveal cones from their peripheral counterparts. Further analysis of predicted ligand-receptor interactions suggested a potential role for Muller glia in supporting the maturation of foveal cones. Together, these results provide valuable insights into foveal development, structure, and evolution.

Serotonin Reduces Belief Stickiness
Serotonin fosters cognitive flexibility, but how, exactly, remains unclear. We show that serotonin reduces belief stickiness: the tendency to get "stuck" in a belief about the state of the world despite incoming contradicting evidence. Participants performed a task assessing belief stickiness in a randomized, double-blind, placebo-controlled study using a single dose of the selective serotonin reuptake inhibitor (SSRI) escitalopram. In the escitalopram group, higher escitalopram plasma levels reduced belief stickiness more, resulting in better inference about the state of the world. Moreover, participants with sufficiently high escitalopram plasma levels had less belief stickiness, and therefore better state inference, than participants on placebo. Exaggerated belief stickiness is exemplified by obsessions: "sticky" thoughts that persist despite contradicting evidence. Indeed, participants with more obsessions had greater belief stickiness, and therefore worse state inference. The opposite relations of escitalopram and obsessions with belief stickiness may explain the therapeutic effect of SSRIs in obsessive-compulsive disorder.

Computational demonstration of spinal circuit that modulates γ-MN activity via α-MN collateral mitigates the inevitable disruptions from velocity-dependent stretch reflexes during voluntary movements
The primary motor cortex does not uniquely or directly produce -MN drive to muscles during voluntary movement. Rather, -MN drive emerges from the synthesis and competition among excitatory and inhibitory inputs from multiple descending tracts, spinal interneurons, sensory inputs, and proprioceptive afferents. One such fundamental input are velocity-dependent stretch reflexes in lengthening (antagonist) muscles, which the shortening (agonist) muscles are thought to inhibit to allow voluntary movement. It remains an open question, however, the extent to which velocity-dependent stretch reflexes disrupt voluntary movement, and whether and how they should be inhibited in limbs with numerous mono- and multi-articular muscles where agonist and antagonist roles become unclear and can switch during a movement. We address these long-standing fundamental questions using 3D movements against gravity in a 25-muscle computational model of a Rhesus Macaque arm. After simulating 1,100 distinct movements across the workspace of the arm with feedforward -MN commands, we computed the kinematic disruptions to the arm endpoint trajectories caused by adding positive homonymous muscle velocity feedback (i.e., simple velocity-dependent stretch reflexes ) at different static gains to the feedforward -MN drive (without reciprocal inhibition). We found that arm endpoint trajectories were disrupted in surprisingly movement-specific, typically large and variable ways, and could even change movement direction as the reflex gain increased. In contrast, these disruptions became small at all reflex gains when the velocity-dependent stretch reflexes were simply scaled by the -MN drive to each muscle (equivalent to an -MN excitatory collateral to its homologous {gamma}-MNs , but distinct from -{gamma} co-activation ). We argue this circuitry is more neuroanatomically tenable, generalizable, and scalable than -{gamma} co-activation and movement-specific reciprocal inhibition. In fact, we propose that this mechanism at the homonymous propriospinal level could be a critical low-level enabler of learning via cerebellar and cortical mechanisms by locally and automatically regulating the highly nonlinear neuro-musculo-skeletal mechanics of the limb. This propriospinal mechanism also provides a powerful paradigm that may begin to clarify how dysregulation of {gamma}-MN drive can result in disruptions of voluntary movement in neurological conditions.

Maternal dietary deficiencies in folic acid or choline reduce primary neuron viability after exposure to hypoxia through increased levels of apoptosis
Stoke is the leading cause of death and disability globally. By addressing modifiable risk factors, particularly nutrition, the prevalence of stroke and its dire consequences can be mitigated. One-carbon (1C) metabolism is a critical biosynthetic process that is involved in neural tube closure, neuronal plasticity, and cellular proliferation in the developing embryo. Folic acid and choline are two active components of 1C metabolism, we have previously demonstrated that maternal dietary deficiencies in folic acid or choline worsen stroke outcomes in offspring. However, there is insufficient data to understand the neuronal mechanisms involved. We exposed embryonic neurons of offspring, whom mothers were on folic acid or choline deficient diets, to hypoxia conditions for 6 hours and return to normoxic conditions for 24 hours to model an ischemic stroke and reperfusion injury. To determine whether increased levels of either folic acid or choline can rescue reduced neuronal viability, we supplemented cell media with folic acid and choline prior to and after exposure to hypoxia. Our results suggest that maternal dietary deficiencies in either folic acid or choline during pregnancy negatively impacts offspring neuronal viability after hypoxia. Furthermore, increasing levels of folic acid or choline prior to and after hypoxia have a beneficial impact on neuronal viability. The findings contribute to our understanding of the intricate interplay between maternal dietary factors, 1C metabolism, and the outcome of offspring to hypoxic events, emphasizing the potential for nutritional interventions in mitigating adverse outcomes.

Lifestyle and brain health determinants of word-finding failures in healthy ageing
Cognitive decline associated with healthy ageing is complex and multifactorial: vascular and lifestyle factors uniquely and jointly contribute to distinct neurocognitive trajectories of ageing. To evaluate existing accounts of neurocognitive ageing that propose mechanisms of compensation, maintenance or reserve, studies should explore how various known brain-based and lifestyle factors intersect to better understand cognitive decline. Here, we bring together brain function, structure, perfusion, and cardiorespiratory fitness to investigate a well-documented, prominent cognitive challenge for older adults: word-finding failures. Commonality analysis on 73 neurologically healthy older adults revealed that functional activation of language networks associated with tip-of-the-tongue states is in part determined by age and, interestingly, cardiorespiratory fitness levels. Age-associated atrophy and perfusion in regions other than those showing functional differences accounted for variance in tip-of-the-tongue states. Our findings can be interpreted in the context of the classic models of neurocognitive ageing, with mechanisms of compensation and reserve interacting with each other.

Imaging Electrical Activity of Retinal Ganglion Cells with Fluores-cent Voltage and Calcium Indicator Proteins in Retinal Degenera-tive rd1 Blind Mice
In order to understand the retinal network, it is essential to identify functional connectivity among retinal neurons. For this purpose, imaging neuronal activity through fluorescent indicator proteins has been a promising approach offering simulta-neous measurements of neuronal activities from different regions of the circuit. In this study, we used genetically encoded voltage and calcium indicators, Bongwoori-R3 and GCaMP6f, to visualize membrane voltage and calcium dynamics in the form of the spatial map within retinal ganglion cells from retina tissues of the photoreceptor degenerated rd1 mice. Retinal voltage imaging confirmed current-evoked responses from somatic spiking and intercellular conduction, while calcium imag-ing showed current evoked changes in calcium concentrations of presynaptic neurons. These results indicate that the combi-nation of fluorescent protein sensors and high-speed imaging methods permits imaging electrical activity with cellular preci-sion and millisecond resolution. Hence, we expect our method will provide a potent experimental platform for the study of retinal signaling pathways as well as the development of retinal stimulation strategies in visual prosthesis.

Proactive and reactive construction of memory-based preferences
We are often faced with decisions we have never encountered before, requiring us to infer possible outcomes before making a choice. Computational theories suggest that one way to make these types of decisions is by accessing and linking related experiences stored in memory. Past work has shown that such memory-based preference construction can occur at a number of different timepoints relative to the moment a decision is made. Some studies have found that memories are integrated at the time a decision is faced (reactively) while others found that memory integration happens earlier, when memories are encoded (proactively). Here we offer a resolution to this inconsistency. We demonstrate behavioral and neural evidence for both strategies and for how they tradeoff rationally depending on the associative structure of memory. Using fMRI to decode patterns of brain responses unique to categories of images in memory, we found that proactive memory access is more common and allows more efficient inference. However, participants also use reactive access when choice options are linked to more numerous memory associations. Together, these results indicate that the brain judiciously conducts proactive inference by accessing memories ahead of time in conditions when this strategy is most favorable.

A Pose-Informed De-Noising Diffusion Model for Adult Naturalistic EEG Signals
Artifact contamination in EEG (electroencephalogram) signals is a significant problem, especially in naturalistic settings where participants can move freely. This contamination stems from various sources like eye movements, muscle activity, sweat, and electrical interference, whose effects differ greatly from each other. Traditional denoising methods, such as Independent Component Analysis, are limited because they assume a linear relationship between the source of the artifacts and the EEG signals, and often require the dominance of one noise source over others. Moreover, these methods need expert knowledge in EEG analysis and lack an objective standard for evaluation. To overcome these challenges, we propose two innovations: Firstly, we introduce the use of "video-estimated" pose coordinates, the x and y positions of different body points (like wrists, eyes, and ankles), to assist in the EEG denoising process. Secondly, we present a denoising diffusion model, EEG-DDM, that utilizes both the contaminated EEG signals and these pose coordinates to effectively denoise the EEG. Our findings show that incorporating keypoints (pose coordinates) improves denoising performance and helps maintain cross-spatial dependencies in the data. Additionally, we enhance human interpretability of the process by displaying saliency maps generated by our model, which explain the contributions of these keypoints in the denoising process

Injectable 3D microcultures enable intracerebral transplantation of mature neurons directly reprogrammed from patient fibroblasts
Direct reprogramming of somatic cells into induced neurons (iNs) has become an attractive strategy for the generation of patient-specific neurons for disease modeling and regenerative neuroscience. To this end, adult human dermal fibroblasts (hDFs) present one of the most relevant cell sources. However, iNs generated from adult hDFs using two-dimensional (2D) cultures poorly survive transplantation into the adult brain in part due to the need for enzymatic or mechanical cellular dissociation before transplantation. Three-dimensional (3D) culturing methodologies have the potential to overcome these issues but have largely been unexplored for the purposes of direct neuronal reprogramming. Here we report a strategy for direct in vitro reprogramming of adult hDFs inside suspension 3D microculture arrays into induced DA neurospheroids (iDANoids). We show that iDANoids express neuronal and DA markers and are capable of firing mature action potentials and releasing dopamine. Importantly, they can be gently harvested and transplanted into the brain of a Parkinson's disease rat model to reproducibly generate functionally integrated neuron-rich grafts. The 3D culturing approach presented here thus eliminates a major bottleneck in direct neuronal reprogramming field and, due to its simplicity and versatility, could readily be adapted as a culturing platform used for a broad range of transplantation studies as well as disease modeling.

Neurogenesis and neuronal migration in hypothalamic vasopressinergic magnocellular nuclei of the adult rat
In restricted mammalian brain regions, cell proliferation and migration continue postnatally and throughout adulthood. Here we show, using immunohistochemical reaction (ir) against arginine vasopressin (AVP), neurophysin II, glial fibrillar acidic protein (GFAP), cell division and early neuronal markers Ki67 and doublecortin (DCX) respectively, and neuroanatomical analysis on the rat brain in serial sections of coronal, sagittal, horizontal and septo-temporal oblique orientations from adult rats, that neurons from hypothalamic supraoptic (SON) and paraventricular (PVN) nuclei are dispersed along visible tangential routes to other subcortical regions, guided by AVP-ir cell chains and axon scaffolds. Using 5'-bromo-2'-deoxyuridine (BrdU) injection in adult rats followed by BrdU-ir, we observed numerous twin-nuclei within SON and PVN, with some double-labeled for AVP. Chronic water deprivation significantly increased the BrdU+ nuclei within both SON and PVN. Immunofluorescent reaction showed double labeling of AVP/DCX within SON and PVN. Interestingly, NeuN, a mature neuron marker, was largely absent in SON and PVN, but present in neurons within adjacent hypothalamic regions. These findings provide evidence that adult neurogenesis and migration occur in hypothalamic vasopressinergic nuclei and reveal tangential migration routes of AVP-ir neuronal chains and ascending axonal scaffolds in adult rats.

Dynamics and bifurcation structure of a mean-field model of adaptive exponential integrate-and-fire networks
The study of brain activity spans diverse scales and levels of description, and requires the development of computational models alongside experimental investigations to explore integrations across scales. The high dimensionality of spiking networks presents challenges for understanding their dynamics. To tackle this, a mean-field formulation offers a potential approach for dimensionality reduction while retaining essential elements. Here, we focus on a previously developed mean-field model of Adaptive Exponential (AdEx) networks, utilized in various research works. We provide a systematic investigation of its properties and bifurcation structure, which was not available for this model. We show that this provides a comprehensive description and characterization of the model to assist future users in interpreting their results. The methodology includes model construction, stability analysis, and numerical simulations. Finally, we offer an overview of dynamical properties and methods to characterize the mean-field model, which should be useful for for other models.

Oligodendrocytes and neurons contribute to amyloid-β deposition in Alzheimer's disease
In Alzheimer's disease (AD), amyloid-{beta} (A{beta}) is thought to be of neuronal origin. However, in single-cell RNAseq datasets from mouse and human, we found transcripts of amyloid precursor protein (APP) and the amyloidogenic-processing machinery equally abundant in oligodendrocytes (OLs). By cell-type-specific deletion of Bace1 in a humanized knock-in AD model, APPNLGF, we demonstrate that almost a third of cortical A{beta} deposited in plaques is derived from OLs. However, excitatory projection neurons must provide a threshold level of A{beta} production for plaque deposition to occur and for oligodendroglial A{beta} to co-aggregate. Indeed, very few plaques are deposited in the absence of neuronally-derived A{beta}, although soluble A{beta} species are readily detected, especially in subcortical white matter. Our data identify OLs as a source of A{beta} in vivo and further underscore a non-linear relationship between cellular A{beta} production and resulting plaque formation. Ultimately, our observations are relevant for therapeutic strategies aimed at disease prevention in AD.