Exploring the relationship between emotion regulation, inhibitory control, and eating psychopathology in a non-clinical sample.

OBJECTIVE: The present study aimed to explore the relationship between difficulties in emotion regulation and deficits in inhibitory control, and the role of these processes in eating psychopathology in a non-clinical sample. We also explored the specificity in which deficits in inhibitory control may underlie eating psychopathology, namely whether they can be conceptualised as context specific or more extensive in nature. METHOD: Participants were 107 healthy individuals recruited at a major Portuguese university, aged between 18 and 43 years-old (M = 21.23, SD = 4.79). Two computerised neuropsychological tasks (i.e., emotional go/no-go and food go/no-go tasks) were used to assess response inhibition in the presence of general versus context-specific stimuli. A set of self-report measures was used to assess variables of interest such as emotion regulation and eating psychopathology. RESULTS: Results indicated higher response inhibition deficits among participants with higher difficulties in emotion regulation comparing to those with lower difficulties in emotion regulation, particularly in the context of food-related stimuli. In addition, the relationship between difficulties in emotion regulation and eating psychopathology was moderated by inhibitory control deficits in both the context of food and pleasant stimuli. CONCLUSIONS: The present findings highlight inhibitory control as an important process underlying the relationship between difficulties in emotion regulation and eating psychopathology in non-clinical samples. Findings have important implications for clinical practice and the prevention of eating psychopathology in healthy individuals and individuals with eating disorders.

Emerging Role of miR-21-5p in Neuron-Glia Dysregulation and Exosome Transfer Using Multiple Models of Alzheimer's Disease.

Alzheimer's disease (AD) is a neurodegenerative disorder associated with neuron-glia dysfunction and dysregulated miRNAs. We previously reported upregulated miR-124/miR-21 in AD neurons and their exosomes. However, their glial distribution, phenotypic alterations and exosomal spread are scarcely documented. Here, we show glial cell activation and miR-21 overexpression in mouse organotypic hippocampal slices transplanted with SH-SY5Y cells expressing the human APP695 Swedish mutation. The upregulation of miR-21 only in the CSF from a small series of mild cognitive impairment (MCI) AD patients, but not in non-AD MCI individuals, supports its discriminatory potential. Microglia, neurons, and astrocytes differentiated from the same induced pluripotent stem cells from PSEN1ΔE9 AD patients all showed miR-21 elevation. In AD neurons, miR-124/miR-21 overexpression was recapitulated in their exosomes. In AD microglia, the upregulation of iNOS and miR-21/miR-146a supports their activation. AD astrocytes manifested a restrained inflammatory profile, with high miR-21 but low miR-155 and depleted exosomal miRNAs. Their immunostimulation with C1q + IL-1α + TNF-α induced morphological alterations and increased S100B, inflammatory transcripts, sAPPß, cytokine release and exosomal miR-21. PPARα, a target of miR-21, was found to be repressed in all models, except in neurons, likely due to concomitant miR-125b elevation. The data from these AD models highlight miR-21 as a promising biomarker and a disease-modifying target to be further explored.

Vulnerability through the Eyes of People Attended by a Portuguese Community-Based Association: A Thematic Analysis.

Vulnerability is associated with the individual's social and biological conditions, but also the conditions of their enveloping environment and society, leading to terms such as vulnerable populations or risk groups. This study aimed to give a voice to people with experiences of vulnerability and explore their perspectives, using a descriptive qualitative design. Purportedly vulnerable adults were recruited and interviewed with semi-structured questions on vulnerability. Data were organized, using WebQDA software, and submitted to thematic content analysis, as proposed by Clark and Braun, which generated a thematic tree. The study included six men and six women with a mean age of 43.8 [SD = 14.17] years old. Thematic analysis generated three themes: (1) Conceptions about vulnerability, (2) Barriers imposed by vulnerability, and (3) Strategies for dealing with vulnerability. The results highlight that vulnerability is a highly dynamic process of openness to circumstances that influence individual outcomes. However, there is a lack of conceptual clarity. Although being vulnerable is perceived as something negative, we need to transform the social mindset, because vulnerability also has the potential to change priorities in life for the better.

Intrathecal Injection of the Secretome from ALS Motor Neurons Regulated for miR-124 Expression Prevents Disease Outcomes in SOD1-G93A Mice.

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease with short life expectancy and no effective therapy. We previously identified upregulated miR-124 in NSC-34-motor neurons (MNs) expressing human SOD1-G93A (mSOD1) and established its implication in mSOD1 MN degeneration and glial cell activation. When anti-miR-124-treated mSOD1 MN (preconditioned) secretome was incubated in spinal cord organotypic cultures from symptomatic mSOD1 mice, the dysregulated homeostatic balance was circumvented. To decipher the therapeutic potential of such preconditioned secretome, we intrathecally injected it in mSOD1 mice at the early stage of the disease (12-week-old). Preconditioned secretome prevented motor impairment and was effective in counteracting muscle atrophy, glial reactivity/dysfunction, and the neurodegeneration of the symptomatic mSOD1 mice. Deficits in corticospinal function and gait abnormalities were precluded, and the loss of gastrocnemius muscle fiber area was avoided. At the molecular level, the preconditioned secretome enhanced NeuN mRNA/protein expression levels and the PSD-95/TREM2/IL-10/arginase 1/MBP/PLP genes, thus avoiding the neuronal/glial cell dysregulation that characterizes ALS mice. It also prevented upregulated GFAP/Cx43/S100B/vimentin and inflammatory-associated miRNAs, specifically miR-146a/miR-155/miR-21, which are displayed by symptomatic animals. Collectively, our study highlights the intrathecal administration of the secretome from anti-miR-124-treated mSOD1 MNs as a therapeutic strategy for halting/delaying disease progression in an ALS mouse model.

The mediating role of self-criticism, experiential avoidance and negative urgency on the relationship between ED-related symptoms and difficulties in emotion regulation.

OBJECTIVE: Difficulties in emotion regulation are thought to play a transdiagnostic role across eating disorders (ED). In the current study, we explored with a path analysis the mediating role of self-criticism, experiential avoidance and negative urgency on the relationship between ED-related symptoms and dimensions of difficulties in emotion regulation. METHOD: Participants were 103 female outpatients recruited at a Portuguese ED hospital unit, diagnosed with an ED, aged 14-60 years old (M = 28.0, SD = 10.5), body mass index (BMI) ranging from 11.72 to 39.44 (M = 20.1, SD = 5.4). RESULTS: The path analysis resulted in a model with an adequate fit to the data (SRMR = 0.05; RMSEA = 0.07 [0.00, 0.12], PCLOSE = 0.269; TLI = 0.97; IFI = 0.99; GFI = 0.95). A final model in which the relationship between ED-related symptoms and dimensions of difficulties in emotion regulation was mediated by self-criticism, experiential avoidance and negative urgency, accounted for a variance of 71% for strategies, 57% for non-acceptance, 62% for impulses, 56% for goals and 20% for clarity. CONCLUSION: Results suggest that self-criticism, experiential avoidance and negative urgency, combined, are relevant in the relationship between ED-related symptoms and difficulties in emotion regulation. ED treatment and emotion regulation skills may be enhanced through the inclusion of specific components that target self-criticism, experiential avoidance and negative urgency, as they become prominent during the therapeutic process.

Challenges in the Development of Drug Delivery Systems Based on Small Extracellular Vesicles for Therapy of Brain Diseases.

Small extracellular vesicles (sEVs) have ∼30-200 nm diameter size and may act as carriers of different cargoes, depending on the cell of origin or on the physiological/pathological condition. As endogenous nanovesicles, sEVs are important in intercellular communication and have many of the desirable features of an ideal drug delivery system. sEVs are naturally biocompatible, with superior targeting capability, safety profile, nanometric size, and can be loaded with both lipophilic and hydrophilic agents. Because of their biochemical and physical properties, sEVs are considered a promising strategy over other delivery vehicles in the central nervous system (CNS) since they freely cross the blood-brain barrier and they can be directed to specific nerve cells, potentiating a more precise targeting of their cargo. In addition, sEVs remain stable in the peripheral circulation, making them attractive nanocarrier systems to promote neuroregeneration. This review focuses on the recent progress in methods for manufacturing, isolating, and engineering sEVs that can be used as a therapeutic strategy to overcome neurodegeneration associated with pathologies of the CNS, with particular emphasis on Alzheimer's, Parkinson's, and amyotrophic lateral sclerosis diseases, as well as on brain tumors.

Differences in Immune-Related Genes Underlie Temporal and Regional Pathological Progression in 3xTg-AD Mice.

The prevalence of Alzheimer's disease (AD), the most common cause of age-associated dementia, is estimated to increase over the next decades. Evidence suggests neuro-immune signaling deregulation and risk genes beyond the amyloid-ß (Aß) deposition in AD pathology. We examined the temporal profile of inflammatory mediators and microglia deactivation/activation in the brain cortex and hippocampus of 3xTg-AD mice at 3- and 9-month-old. We found upregulated APP processing, decreased expression of CD11b, CX3CR1, MFG-E8, TNF-α, IL-1ß, MHC-II and C/EBP-α and increased miR-146a in both brain regions in 3-month-old 3xTG-AD mice, suggestive of a restrictive regulation. Enhanced TNF-α, IL-1ß, IL-6, iNOS, SOCS1 and Arginase 1 were only present in the hippocampus of 9-month-old animals, though elevation of HMGB1 and reduction of miR-146a and miR-124 were common features in the hippocampus and cortex regions. miR-155 increased early in the cortex and later in both regions, supporting its potential as a biomarker. Candidate downregulated target genes by cortical miR-155 included Foxo3, Runx2 and CEBPß at 3 months and Foxo3, Runx2 and Socs1 at 9 months, which are implicated in cell survival, but also in Aß pathology and microglia/astrocyte dysfunction. Data provide new insights across AD state trajectory, with divergent microglia phenotypes and inflammatory-associated features, and identify critical targets for drug discovery and combinatorial therapies.

Overexpression of miR-124 in Motor Neurons Plays a Key Role in ALS Pathological Processes.

miRNA(miR)-124 is an important regulator of neurogenesis, but its upregulation in SOD1G93A motor neurons (mSOD1 MNs) was shown to associate with neurodegeneration and microglia activation. We used pre-miR-124 in wild-type (WT) MNs and anti-miR-124 in mSOD1 MNs to characterize the miR-124 pathological role. miR-124 overexpression in WT MNs produced a miRNA profile like that of mSOD1 MNs (high miR-125b; low miR-146a and miR-21), and similarly led to early apoptosis. Alterations in mSOD1 MNs were abrogated with anti-miR-124 and changes in their miRNAs mostly recapitulated by their secretome. Normalization of miR-124 levels in mSOD1 MNs prevented the dysregulation of neurite network, mitochondria dynamics, axonal transport, and synaptic signaling. Same alterations were observed in WT MNs after pre-miR-124 transfection. Secretome from mSOD1 MNs triggered spinal microglia activation, which was unno-ticed with that from anti-miR-124-modulated cells. Secretome from such modulated MNs, when added to SC organotypic cultures from mSOD1 mice in the early symptomatic stage, also coun-teracted the pathology associated to GFAP decrease, PSD-95 and CX3CL1-CX3CR1 signaling im-pairment, neuro-immune homeostatic imbalance, and enhanced miR-124 expression levels. Data suggest that miR-124 is implicated in MN degeneration and paracrine-mediated pathogenicity. We propose miR-124 as a new therapeutic target and a promising ALS biomarker in patient sub-populations.

Understanding Uncontrolled Eating after Bariatric Surgery: The Role of Excessive Skin and Body Image Shame.

Excess skin and disordered eating behaviors are referred to as some of the major negative consequences of bariatric surgery as well as body image shame. This study sought to explore how discomfort with excessive skin, body image shame, psychological distress, eating-related psychopathology, and negative urgency interact to understand uncontrolled eating among woman submitted to bariatric surgery. A cross-sectional sample of 137 women was evaluated postoperatively through self-report questionnaires assessing discomfort with excess skin, body image shame, eating-related psychopathology, negative urgency, and uncontrolled eating in a hospital center in the north of Portugal. Pearson correlations and Structural Equation Modeling (SEM) were performed. Body image shame mediated the relationship between discomfort with excess skin and eating-related psychopathology. In turn, the relationship between eating-related psychopathology and uncontrolled eating was mediated by negative urgency. This study highlights the impact of excess skin and body image shame on eating behavior post-bariatric-surgery. Considering the proven impact of uncontrolled eating on weight-loss results post-surgery, understanding the mechanisms underlying this problem is highly important. Our findings provide helpful insight for multidisciplinary teams committed to providing care to bariatric patients struggling with body image and eating difficulties.

Recovery of Depleted miR-146a in ALS Cortical Astrocytes Reverts Cell Aberrancies and Prevents Paracrine Pathogenicity on Microglia and Motor Neurons.

Reactive astrocytes in Amyotrophic Lateral Sclerosis (ALS) change their molecular expression pattern and release toxic factors that contribute to neurodegeneration and microglial activation. We and others identified a dysregulated inflammatory miRNA profile in ALS patients and in mice models suggesting that they represent potential targets for therapeutic intervention. Such cellular miRNAs are known to be released into the secretome and to be carried by small extracellular vesicles (sEVs), which may be harmful to recipient cells. Thus, ALS astrocyte secretome may disrupt cell homeostasis and impact on ALS pathogenesis. Previously, we identified a specific aberrant signature in the cortical brain of symptomatic SOD1-G93A (mSOD1) mice, as well as in astrocytes isolated from the same region of 7-day-old mSOD1 mice, with upregulated S100B/HMGB1/Cx43/vimentin and downregulated GFAP. The presence of downregulated miR-146a on both cases suggests that it can be a promising target for modulation in ALS. Here, we upregulated miR-146a with pre-miR-146a, and tested glycoursodeoxycholic acid (GUDCA) and dipeptidyl vinyl sulfone (VS) for their immunoregulatory properties. VS was more effective in restoring astrocytic miR-146a, GFAP, S100B, HMGB1, Cx43, and vimentin levels than GUDCA, which only recovered Cx43 and vimentin mRNA. The miR-146a inhibitor generated typical ALS aberrancies in wild type astrocytes that were abolished by VS. Similarly, pre-miR-146a transfection into the mSOD1 astrocytes abrogated aberrant markers and intracellular Ca2+ overload. Such treatment counteracted miR-146a depletion in sEVs and led to secretome-mediated miR-146a enhancement in NSC-34-motor neurons (MNs) and N9-microglia. Secretome from mSOD1 astrocytes increased early/late apoptosis and FGFR3 mRNA in MNs and microglia, but not when derived from pre-miR-146a or VS-treated cells. These last strategies prevented the impairment of axonal transport and synaptic dynamics by the pathological secretome, while also averted microglia activation through either secretome, or their isolated sEVs. Proteomic analysis of the target cells indicated that pre-miR-146a regulates mitochondria and inflammation via paracrine signaling. We demonstrate that replenishment of miR-146a in mSOD1 cortical astrocytes with pre-miR-146a or by VS abrogates their phenotypic aberrancies and paracrine deleterious consequences to MNs and microglia. These results propose miR-146a as a new causal and emerging therapeutic target for astrocyte pathogenic processes in ALS.

Eating behaviors and weight outcomes in bariatric surgery patients amidst COVID-19.

BACKGROUND: Recent studies suggest that eating habits are an area particularly affected by the lockdown imposed by many countries to curb the COVID-19 epidemic. Individuals that received bariatric surgery may represent a particularly susceptible population to the adverse effects of lockdown for its potential impact on eating, psychological, and weight loss outcomes. OBJECTIVES: This study seeks to investigate the incremental impact of COVID-19 lockdown on treatment outcomes of postbariatric patients in the risk period for weight regain. SETTING: Main hospital center. METHODS: This work uses data from an ongoing longitudinal study of bariatric patients assessed before surgery (T0), 1.5 years after sugery (T1), and 3 years after surgery (T2). Two independent groups were compared: the COVID-19_Group (n = 35) where T0 and T1 assessments were conducted before the pandemic started and T2 assessment was conducted at the end of the mandatory COVID-19 lockdown; and the NonCOVID-19_Group (n = 66), covering patients who completed T0, T1, and T2 assessments before the epidemic began. Assessment included self-report measures for disordered eating, negative urgency, depression, anxiety, stress, and weight outcomes. RESULTS: General linear models for repeated measures showed that the COVID-19_Group presented significantly higher weight concern (F = 8.403, P = .005, ƞ2p = .094), grazing behavior (F = 7.166, P = .009, ƞ2p = .076), and negative urgency (F = 4.522, P = .036, ƞ2p = .05) than the NonCOVID-19_Group. The COVID-19_Group also showed less total weight loss (F = 4.029, P = .05, ƞ2p = .04) and larger weight regain at T2, with more COVID-19_Group participants experiencing excessive weight regain (20% versus 4.5%). CONCLUSION: These results show evidence for the impact of the coronavirus outbreak on eating-related psychopathology and weight outcomes in postbariatric surgery patients.

Exploring Correlates of Loss of Control Eating in a Nonclinical Sample.

OBJECTIVE: Loss of control (LOC) eating has been directly related to the core aspects of the psychopathology of eating disorders and to different dimensions of emotion and behavior regulation and self-criticism. This study investigates a model representing the interplay between these dimensions to understand LOC eating among a nonclinical sample. METHODS: A total of 341 participants, recruited in a college campus (mean age 23.21, SD = 6.02), completed a set of self-report measures assessing LOC eating, weight suppression, psychopathology of eating disorders, depression, negative urgency, emotion regulation difficulties, and self-criticism. Path analysis modeling tested a hypothesized model with 3 paths for LOC eating as follows: (1) psychopathology of eating disorders; (2) emotion and behavior regulation; and (3) interplay between these paths. RESULTS: We found goodness-of-fit indexes to our data: χ2 = 17.11, df = 10, Comparative Fit Index (CFI) = 0.99, Tucker-Lewis index (TLI) = 0.98, Root Mean Square Error Approximation (RMSEA) = 0.045, Standardized Root Mean Square Residual (SRMR) = 0.041, suggesting that: (1) participants with higher weight suppression showed higher degrees of the psychopathology of eating disorders, which was linked to higher levels of LOC eating; (2) self-criticism was a mediator between emotion regulation and depression/negative urgency; (3) self-criticism was a mediator between emotion regulation and disorder eating, which was significantly associated with LOC eating via increased negative urgency. CONCLUSION: Our model shows that LOC eating occurs for individuals with the psychopathology of higher eating disorders who experience depressive symptoms and act rashly under distress for their inability to cope adequately with negative feelings of self-devaluation. These findings point to the importance of negative self-evaluations and feelings of inadequacy or worthlessness to understand LOC eating among college students.

Designer Cathinones N-Ethylhexedrone and Buphedrone Show Different In Vitro Neurotoxicity and Mice Behaviour Impairment.

N-Ethylhexedrone (NEH) and buphedrone (Buph) are emerging synthetic cathinones (SC) with limited information about their detrimental effects within central nervous system. Objectives: To distinguish mice behavioural changes by NEH and Buph and validate their differential harmful impact on human neurons and microglia. In vivo safety data showed the typical induced behaviour of excitation and stereotypies with 4-64 mg/kg, described for other SC. Buph additionally produced jumping and aggressiveness signs, while NEH caused retropulsion and circling. Transient reduction in body-weight gain was obtained with NEH at 16 mg/kg and induced anxiolytic-like behaviour mainly with Buph. Both drugs generated place preference shift in mice at 4 and 16 mg/kg, suggestive of abuse potential. In addition, mice withdrawn NEH displayed behaviour suggestive of depression, not seen with Buph. When tested at 50-400 µM in human nerve cell lines, NEH and Buph caused neuronal viability loss at 100 µM, but only NEH produced similar results in microglia, indicating different cell susceptibilities. NEH mainly induced microglial late apoptosis/necrosis, while Buph caused early apoptosis. NEH was unique in triggering microglia shorter/thicker branches indicative of cell activation, and more effective in increasing microglial lysosomal biogenesis (100 µM vs. 400 µM Buph), though both produced the same effect on neurons at 400 µM. These findings indicate that NEH and Buph exert neuro-microglia toxicities by distinct mechanisms and highlight NEH as a specific inducer of microglia activation. Buph and NEH showed in vivo/in vitro neurotoxicities but enhanced specific NEH-induced behavioural and neuro-microglia dysfunctionalities pose safety concerns over that of Buph.

Astrocyte regional diversity in ALS includes distinct aberrant phenotypes with common and causal pathological processes.

Astrocytes are major contributors of motor neuron (MN) degeneration in amyotrophic lateral sclerosis (ALS). We investigated whether regional and cell maturation differences influence ALS astrocyte malfunction. Spinal and cortical astrocytes from SOD1G93A (mSOD1) 7-day-old mice were cultured for 5 and 13 days in vitro (DIV). Astrocyte aberrancies predominated in 13DIV cells with region specificity. 13DIV cortical mSOD1 astrocytes showed early morphological changes and a predominant reactive and inflammatory phenotype, while repressed proteins and genes were found in spinal cells. Inflammatory-associated miRNAs, e.g. miR-155/miR-21/miR-146a, were downregulated in the first and upregulated in the later ones. Interestingly, depleted miR-155/miR-21/miR-146a in small extracellular vesicles (sEVs/exosomes) was a common pathological feature. Cortical mSOD1 astrocytes induced late apoptosis and kinesin-1 downregulation in mSOD1 NSC-34 MNs, whereas spinal cells upregulated dynein, while decreased nNOS and synaptic-related genes. Both regional-distinct mSOD1 astrocytes enhanced iNOS gene expression in mSOD1 MNs. We provide information on the potential contribution of astrocytes to ALS bulbar-vs. spinal-onset pathology, local influence on neuronal dysfunction and their shared miRNA-depleted exosome trafficking. These causal and common features may have potential therapeutic implications in ALS. Future studies should clarify if astrocyte-derived sEVs are active players in ALS-related neuroinflammation and glial activation.

Microglia Susceptibility to Free Bilirubin Is Age-Dependent.

Increased concentrations of unconjugated bilirubin (UCB), namely its free fraction (Bf), in neonatal life may cause transient or definitive injury to neurons and glial cells. We demonstrated that UCB damages neurons and glial cells by compromising oligodendrocyte maturation and myelination, and by activating astrocytes and microglia. Immature neurons and astrocytes showed to be especially vulnerable. However, whether microglia susceptibility to UCB is also age-related was never investigated. We developed a microglia culture model in which cells at 2 days in vitro (2DIV) revealed to behave as the neonatal microglia (amoeboid/reactive cells), in contrast with those at 16DIV microglia that performed as aged cells (irresponsive/dormant cells). Here, we aimed to unveil whether UCB-induced toxicity diverged from the young to the long-cultured microglia. Cells were isolated from the cortical brain of 1- to 2-day-old CD1 mice and incubated for 24 h with 50/100 nM Bf levels, which were associated to moderate and severe neonatal hyperbilirubinemia, respectively. These concentrations of Bf induced early apoptosis and amoeboid shape in 2DIV microglia, while caused late apoptosis in 16DIV cells, without altering their morphology. CD11b staining increased in both, but more markedly in 2DIV cells. Likewise, the gene expression of HMGB1, a well-known alarmin, as well as HMGB1 and GLT-1-positive cells, were enhanced as compared to long-maturated microglia. The CX3CR1 reduction in 2DIV microglia was opposed to the 16DIV cells and suggests a preferential Bf-induced sickness response in younger cells. In conformity, increased mitochondrial mass and NO were enhanced in 2DIV cells, but unchanged or reduced, respectively, in the 16DIV microglia. However, 100 nM Bf caused iNOS gene overexpression in 2DIV and 16DIV cells. While only arginase 1/IL-1ß gene expression levels increased upon 50/100 nM Bf treatment in long-maturated microglia, MHCII/arginase 1/TNF-α/IL-1ß/IL-6 (>10-fold) were upregulated in the 2DIV microglia. Remarkably, enhanced inflammatory-associated microRNAs (miR-155/miR-125b/miR-21/miR-146a) and reduced anti-inflammatory miR-124 were found in young microglia by both Bf concentrations, while remained unchanged (miR/21/miR-125b) or decreased (miR-155/miR-146a/miR-124) in aged cells. Altogether, these findings support the neurodevelopmental susceptibilities to UCB-induced neurotoxicity, the most severe disabilities in premature babies, and the involvement of immune-inflammation neonatal microglia processes in poorer outcomes.

Human iPSC-Derived Hippocampal Spheroids: An Innovative Tool for Stratifying Alzheimer Disease Patient-Specific Cellular Phenotypes and Developing Therapies.

The hippocampus is important for memory formation and is severely affected in the brain with Alzheimer disease (AD). Our understanding of early pathogenic processes occurring in hippocampi in AD is limited due to tissue unavailability. Here, we report a chemical approach to rapidly generate free-floating hippocampal spheroids (HSs), from human induced pluripotent stem cells. When used to model AD, both APP and atypical PS1 variant HSs displayed increased Aß42/Aß40 peptide ratios and decreased synaptic protein levels, which are common features of AD. However, the two variants differed in tau hyperphosphorylation, protein aggregation, and protein network alterations. NeuroD1-mediated gene therapy in HSs-derived progenitors resulted in modulation of expression of numerous genes, including those involved in synaptic transmission. Thus, HSs can be harnessed to unravel the mechanisms underlying early pathogenic changes in the hippocampi of AD patients, and provide a robust platform for the development of therapeutic strategies targeting early stage AD.