Yadong Huang

UCSF University of California, San Francisco | UCSF · Gladstone Institute

Despite strong evidence supporting the involvement of both apolipoprotein E4 (APOE4) and microglia in Alzheimer’s Disease (AD) pathogenesis, the effects of microglia on neuronal APOE4-driven AD pathogenesis remain elusive. Here, we examined such effects utilizing microglial depletion in a chimeric model with human neurons in mouse hippocampus. Spec...

Apolipoprotein E4 (APOE4) is the strongest genetic risk factor for late-onset Alzheimer’s disease (LOAD), leading to earlier age of clinical onset and exacerbating pathologies. There is a critical need to identify protective targets. Recently, a rare APOE variant, APOE3-R136S (Christchurch), was found to protect against early-onset AD in a PSEN1-E2...

Several genetic risk factors for Alzheimers Disease (AD) implicate genes involved in lipid metabolism and many of these lipid genes are highly expressed in glial cells. However, the relationship between lipid metabolism in glia and AD pathology remains poorly understood. Through single-nucleus RNA-sequencing of AD brain tissue, we have identified a...

Apolipoprotein E4 (APOE4) is the strongest known genetic risk factor for late-onset Alzheimer’s disease (AD). Conditions of stress or injury induce APOE expression within neurons, but the role of neuronal APOE4 in AD pathogenesis is still unclear. Here we report the characterization of neuronal APOE4 effects on AD-related pathologies in an APOE4-ex...

Apolipoprotein E4 ( APOE4 ) genotype and aging are critical risk factors for Alzheimer’s disease (AD). Aged APOE4 knock-in (APOE4-KI) mice have phenotypes reflecting features of AD. We conducted a large-scale single nucleus RNA-sequencing study to identify cell-type-specific effects of APOE4 on hippocampal gene expression during aging. APOE4-KI mic...

Alzheimer’s Disease (AD) is a complex neurodegenerative disease that gravely affects patients and imposes an immense burden on caregivers. Apolipoprotein E4 (APOE4) has been identified as the most common genetic risk factor for AD, yet the molecular mechanisms connecting APOE4 to AD are not well understood. Past transcriptomic analyses in AD have r...

Alzheimer's disease (AD) is a multifactorial neurodegenerative disorder that involves dysregulation of many cellular and molecular processes. It is notoriously difficult to develop therapeutics for AD due to its complex nature. Nevertheless, recent advancements in imaging technology and the development of innovative experimental techniques have all...

Specific classes of GABAergic neurons play specific roles in regulating information processing in the brain. In the hippocampus, two major classes, parvalbumin-expressing (PV⁺) and somatostatin-expressing (SST⁺), differentially regulate endogenous firing patterns and target subcellular compartments of principal cells. How these classes regulate the...

The evident genetic, pathological and clinical heterogeneity of Alzheimer’s disease (AD) poses challenges for traditional drug development. We conducted a computational drug-repurposing screen for drugs to treat apolipoprotein E4 (APOE4)-related AD. We first established APOE genotype-dependent transcriptomic signatures of AD by analyzing publicly a...

Background: Alzheimer’s disease (AD) is a progressive neurodegenerative disorder and the most common cause of dementia in the United States. In spite of evidence of females having a greater lifetime risk of developing Alzheimer’s Disease (AD) and greater apolipoprotein E4-related (APOE ε4) AD risk compared to males, molecular signatures underlying...

A predominant trigger and driver of sporadic Alzheimer’s disease (AD) is the synergy of brain oxidative stress and glucose hypometabolism starting at early preclinical stages. Oxidative stress damages macromolecules, while glucose hypometabolism impairs cellular energy supply and antioxidant defense. However, the exact cause of AD-associated glucos...

Selective neurodegeneration is a critical causal factor in Alzheimer’s disease (AD); however, the mechanisms that lead some neurons to perish, whereas others remain resilient, are unknown. We sought potential drivers of this selective vulnerability using single-nucleus RNA sequencing and discovered that ApoE expression level is a substantial driver...

Alzheimer’s Disease (AD) is a complex neurodegenerative disease that gravely affects patients and imposes an immense burden on caregivers. Apolipoprotein E4 (APOE4) has been identified as the most common genetic risk factor for AD, yet the molecular mechanisms connecting APOE4 to AD are not well understood. Past transcriptomic analyses in AD have r...

Specific classes of GABAergic neurons are thought to play specific roles in regulating information processing in the brain. In the hippocampus, two major classes - parvalbumin-expressing (PV+) and somatostatin-expressing (SST+) neurons - differentially regulate endogenous firing patterns and target different subcellular compartments of principal ce...

Background Since genetic findings have implicated microglia and TREM2 in the aetiology of neurodegenerative diseases, particularly Alzheimer's disease (AD), there have been numerous studies indicating changes in the levels of sTREM2 in cerebrospinal fluid (CSF) in sporadic and familial disease. Inflammation has also been implicated in depression an...

Background: Alzheimer’s disease (AD) is a progressive neurodegenerative disorder and the most common cause of dementia in the United States. In spite of evidence of females having a greater lifetime risk of developing Alzheimer’s Disease (AD) and greater apolipoprotein E4-related (apoE4) AD risk compared to males, molecular signatures underlying th...

A paramount driver of sporadic Alzheimer’s disease (AD) is the synergy of oxidative stress and glucose hypometabolism in the brain. Oxidative stress damages macromolecules such as DNA, lipids and proteins, whereas glucose hypometabolism impairs cellular energy supply and antioxidant defense; Together, these cellular and functional alterations may b...

Despite its clear impact on Alzheimer’s disease (AD) risk, apolipoprotein (apo) E4’s contributions to AD etiology remain poorly understood. Progress in answering this and other questions in AD research has been limited by an inability to model human-specific phenotypes in an in vivo environment. Here we transplant human induced pluripotent stem cel...

Background: Alzheimer’s disease (AD) is a progressive neurodegenerative disorder and the most common cause of dementia in the United States. In spite of evidence of females having a greater lifetime risk of developing Alzheimer’s Disease (AD) and greater apolipoprotein E4-related (apoE4) AD risk compared to males, molecular signatures underlying th...

In spite of evidence of females having a greater lifetime risk of developing Alzheimer's Disease (AD) and greater apolipoprotein E4-related (apoE4) AD risk compared to males, molecular signatures underlying these findings remain elusive. We took a meta-analysis approach to study gene expression in the brains of 1,084 AD patients and age-matched con...

Understanding why adult hippocampal neurogenesis (AHN) is impaired in Alzheimer's disease (AD) is essential for unravelling its role in pathogenesis. In this issue of Cell Stem Cell, Zheng et al. (2020) report that human tau accumulation in dentate gyrus GABAergic interneurons disrupts AHN and strengthening GABAergic signaling restores AHN and impr...

Abstract Apolipoprotein (apo) E4 is the major genetic risk factor for Alzheimer’s disease (AD), increasing risk and decreasing age of disease onset. Many studies have demonstrated the detrimental effects of apoE4 in varying cellular contexts. However, the underlying mechanisms explaining how apoE4 leads to cognitive decline are not fully understood...

Homozygous APOE3-Christchurch (R136S) mutation protects a presenilin 1 (PSEN1) mutation carrier from developing Alzheimer’s disease until her seventies.

Alzheimer’s disease (AD) is characterized by progressive memory loss, and there is a pressing need to identify early pathophysiological alterations that predict subsequent memory impairment. Hippocampal sharp-wave ripples (SWRs)—electrophysiological signatures of memory reactivation in the hippocampus—are a compelling candidate for this purpose. Mo...

Primary tauopathies are characterized neuropathologically by inclusions containing abnormal forms of the microtubule-associated protein tau (MAPT) and clinically by diverse neuropsychiatric, cognitive, and motor impairments. Autosomal dominant mutations in the MAPT gene cause heterogeneous forms of frontotemporal lobar degeneration with tauopathy (...

Alzheimer's disease (AD) is characterized by progressive memory loss, and there is a pressing need to identify early pathophysiological alterations that predict subsequent memory impairment. Hippocampal sharp-wave ripples (SWRs) - electrophysiological signatures of memory reactivation in the hippocampus - are a compelling candidate for doing so. Mo...

Pathogenic variation in MAPT, GRN, and C9ORF72 accounts for at most only half of frontotemporal lobar degeneration (FTLD) cases with a family history of neurological disease. This suggests additional variants and genes that remain to be identified as risk factors for FTLD. We conducted a case–control genetic association study comparing pathological...

Efforts to develop drugs for Alzheimer's disease (AD) have shown promise in animal studies, only to fail in human trials, suggesting a pressing need to study AD in human model systems. Using human neurons derived from induced pluripotent stem cells that expressed apolipoprotein E4 (ApoE4), a variant of the APOE gene product and the major genetic ri...

Background Alzheimer disease (AD) is a progressive disorder that affects cognitive function. There is increasing support for the role of neuroinflammation and aberrant immune regulation in the pathophysiology of AD. The immunoregulatory human leukocyte antigen (HLA) complex has been linked to susceptibility for a number of neurodegenerative disease...

Summary information for datasets that make up the ADGC merged dataset. Study name, male/female distribution, case/control/missing distribution, and sample size of 30 datasets containing unrelated individuals combined into the full ADGC dataset. (DOCX)

Twenty iterative analyses of the randomly split ADGC + UCSF combined cohort to corroborate top five-allele haplotype associations with AD risk. We randomly split our full ADGC + UCSF cohort (n = 11,381) in half ten times, balancing AD and cognitively normal controls, to determine how often the haplotypes we found to be significant (p < 0.05) in our...

Chemokine CC4 levels are higher in older adults. Chemokine CC4 levels are on average higher with greater age, suggesting higher levels of inflammation in older individuals. Chemokine CC4 levels are quality controlled and transformed as described in S1 Methods. The plotted points are partial residuals with 95% confidence bands provided in shading. (...

ADNI diagnosis and CSF biomarker information. (PDF)

Class I and class II haplotypes with significant risk associations in individual sexes. All significant class I (two-allele) and class II (three-allele) haplotype results (*p < 0.05) for the combined UCSF + ADGC cohort (n = 11,690) when males and females are analyzed separately. Class I and class II haplotypes present in one of the three most signi...

Individual alleles with significant risk associations in individual sexes. All significant loci results (*p < 0.05) for combined UCSF + ADGC cohort (n = 11,690) when males and females are analyzed separately. Alleles present in one of the top three most significant five-allele haplotypes from the combined analysis (A*02:01~B*13:02~DRB1*07:01~DQA1*0...

Detailed acknowledgments for ADNI and ADGC and other samples used in this study. (PDF)

Box-and-whisker plots of AD cognitive and clinical biomarker measures in HLA A*03:01~B*07:02 haplotype noncarriers and carriers in the ADNI cohort. HLA A*03:01~B*07:02 haplotype carriers (n = 3) do not show any significant differences from haplotype noncarriers (n = 67) in a variety of cognitive assessments and measures of biomarkers in CSF in the...

Box-and-whisker plots of AD cognitive and clinical biomarker measures in DR15 haplotype noncarriers and carriers in the ADNI cohort. DR15 haplotype carriers (n = 23) do not show any significant differences from haplotype noncarriers (n = 47) in a variety of cognitive assessments and measures of biomarkers in CSF in the ADNI cohort. The thick line r...

Analysis plan. (DOCX)

HLA A*03:01~B*07:02 haplotype carriers do not show any significant baseline differences on clinical biomarker measures of AD with the exception of CSF amyloid β level. Analysis of patients with baseline AD diagnosis from the ADNI cohort carrying HLA A*03:01~B*07:02 (n = 3) versus haplotype noncarriers (n = 63) shows no significant differences in vo...

HLA DR15 risk haplotype dosage is associated with longitudinal changes in ADAS and RAVLT cognitive test scores. Results from regression models used to determine the effect of dose of HLA risk haplotype DRB1*15:01~DQA1*01:02~DQB1*06:02 on longitudinal changes in ADAS and RAVLT cognitive test scores in cognitively normal, MCI, and AD groups from the...

DR15 haplotype carriers do not show any significant baseline differences on clinical biomarker measures of AD. Analysis of patients with baseline AD diagnosis from the ADNI cohort carrying DR15 (n = 23) versus DR15 noncarriers (n = 47) show no significant differences in volumetric, clinical, cognitive, and biomarker assessments relevant to AD. The...

Box-and-whisker plot of posterior probabilities of imputation for each of five imputed HLA-alleles in the ADGC cohort. The thick line represents the median, box edges represent the first and third quartiles, and whiskers represent the 95% CI. Values higher than 0.75 (dashed line) were included in the present study. Outlier dots are not shown for cl...

List of immune and inflammation-related CSF biomarkers included in the analysis. (DOCX)

Summary statistics for ADNI participants with baseline CSF protein measurements. Descriptive data are summarized by diagnostic category. Values represent the mean ± standard error, percent, or number of participants in a given diagnostic category. Two-tailed p-values were from ANOVA (continuous traits) or chi-square (categorical values) tests by di...

HLA DR15 risk haplotype dosage is associated with baseline levels of chemokine CC-4 in CSF. Regression models were used to determine the effect of HLA risk haplotype DRB1*15:01~DQA1*01:02~DQB1*06:02 dose on cross-sectional CSF levels of chemokine CC-4 in the cognitively normal, MCI, and AD groups of the ADNI cohort are summarized. The beta estimate...

Five-allele haplotypes with significant risk associations in individual sexes. All significant five-allele haplotype results (*p < 0.05) for the combined UCSF + ADGC cohort (n = 11,690) when males and females are analyzed separately. Two of the three most significant five-allele haplotypes from the combined analysis (males + females) were significa...

Frontotemporal dementia (FTD) and other tauopathies characterized by focal brain neurodegeneration and pathological accumulation of proteins are commonly associated with tau mutations. However, the mechanism of neuronal loss is not fully understood. To identify molecular events associated with tauopathy, we studied induced pluripotent stem cell (iP...

Apolipoprotein (apo) E4 is the major genetic risk factor for Alzheimer’s disease (AD), but the mechanism by which it causes cognitive decline is unclear. In knockin (KI) mice, human apoE4 causes age-dependent learning and memory impairments and degeneration of GABAergic interneurons in the hippocampal dentate gyrus. Here we report two functional ap...

Cellular reprogramming using chemically defined conditions, without genetic manipulation, is a promising approach for generating clinically relevant cell types for regenerative medicine and drug discovery. However, small-molecule approaches for inducing lineage-specific stem cells from somatic cells across lineage boundaries have been challenging....

Unlabelled: Apolipoprotein E4 (apoE4) is the major genetic risk factor for Alzheimer's disease (AD). However, the underlying mechanisms are still poorly understood. We previously reported that female apoE4 knock-in (KI) mice had an age-dependent decline in hilar GABAergic interneurons that correlated with the extent of learning and memory deficits...

Understanding the mechanisms underlying neuronal fate determination will provide important insights into brain development and regenerative approaches to neurological diseases. Now in Cell Stem Cell,Masserdotti et al. (2015) use neuronal conversion of astrocytes to dissect transcriptional mechanisms of fate determination and identify circuits that...

Underlying cognitive declines in Alzheimer's disease (AD) are the result of neuron and neuronal process losses due to a wide range of factors. To date, all efforts to develop therapies that target specific AD-related pathways have failed in late-stage human trials. As a result, an emerging consensus in the field is that treatment of AD patients wit...

Apolipoprotein (apo) E4 is expressed in many types of brain cells, is associated with age-dependent decline of learning and memory in humans, and is the major genetic risk factor for AD. To determine whether the detrimental effects of apoE4 depend on its cellular sources, we generated human apoE knock-in mouse models in which the human APOE gene is...

Apolipoprotein (apo) E is a multifunctional protein with central roles in lipid metabolism, neurobiology, and neurodegenerative diseases. It has three major isoforms (apoE2, apoE3, and apoE4) with different effects on lipid and neuronal homeostasis. A major function of apoE is to mediate the binding of lipoproteins or lipid complexes in the plasma...

The present disclosure provides methods of generating neural stem cells from differentiated somatic cells. The present disclosure also provides induced neural stem cells generated using a subject method, as well as differentiated cells generated from a subject induced neural stem cell. A subject neural stem cell, as well as differentiated cells der...

Excitatory and inhibitory balance of neuronal network activity is essential for normal brain function and may be of particular importance to memory. Apolipoprotein (apo) E4 and amyloid-β (Aβ) peptides, two major players in Alzheimer's disease (AD), cause inhibitory interneuron impairments and aberrant neuronal activity in the hippocampal dentate gy...

Tauopathies represent a group of neurodegenerative disorders characterized by the accumulation of pathological TAU protein in brains. We report a human neuronal model of tauopathy derived from induced pluripotent stem cells (iPSCs) carrying a TAU-A152T mutation. Using zinc-finger nuclease-mediated gene editing, we generated two isogenic iPSC lines:...

Apolipoprotein E ε4 (ApoE4) has been associated with an increased risk of Alzheimer's disease (AD), amyloid deposition and hypometabolism. ApoE4 is less prevalent in non-amnestic AD variants suggesting a direct effect on the clinical phenotype. However, the impact of ApoE4 on amyloid burden and glucose metabolism across different clinical AD syndro...

Excitatory and inhibitory balance of neuronal network activity is essential for normal brain function and may be of particular importance to memory. Apolipoprotein (apo) E4 and amyloid-(A) peptides, two major players in Alzheimer's disease (AD), cause inhibitory interneuron impairments and aberrant neuronal activity in the hippocampal dentate gyrus...

Apolipoprotein (apo) E4 is the leading genetic risk factor for Alzheimer's disease (AD), and it has a gene dose-dependent effect on the risk and age of onset of AD. Although apoE4 is primarily produced by astrocytes in the brain, neurons can also produce apoE4 under stress conditions. ApoE4 is known to inhibit neurite outgrowth and spine developmen...

Apolipoprotein (apo) E4 is the major genetic risk factor for Alzheimer's disease (AD). ApoE4 has sex-dependent effects, whereby the risk of developing AD is higher in apoE4-expressing females than males. However, the mechanism underlying the sex difference, in relation to apoE4, is unknown. Previous findings indicate that apoE4 causes age-dependent...

Neuronal processes of hilar GABAergic interneurons differ by sex. A, Quantification of GAD67 immunoreactivity (IR) in the hilus of 1-month-old male and female apoE-KI mice (n = 6 mice per group). Male apoE-KI mice show greater hilar GAD67-IR compared to their female counterparts. ***p<0.001 male apoE-3KI versus female apoE3-KI mice (t-test); ** p<0...

GABAergic interneuronal profiles in the CA3 change as a function of age, sex and apoE genotype. A–H, GABAergic interneurons in the CA3 positive for GAD67 (A, B), somatostatin (C, D), neuropeptide Y (E, F), and parvalbumin (G, H) in fe