Li-Huei Tsai’s research while affiliated with Massachusetts Institute of Technology and other places

What is this page?


This page lists works of an author who doesn't have a ResearchGate profile or hasn't added the works to their profile yet. It is automatically generated from public (personal) data to further our legitimate goal of comprehensive and accurate scientific recordkeeping. If you are this author and want this page removed, please let us know.

Publications (479)


Molecular hallmarks of excitatory and inhibitory neuronal resilience and resistance to Alzheimer's disease
  • Preprint
  • File available

January 2025

·

66 Reads

·

·

·

[...]

·

Winston Hide

Background: A significant proportion of individuals maintain healthy cognitive function despite having extensive Alzheimer's disease (AD) pathology, known as cognitive resilience. Understanding the molecular mechanisms that protect these individuals can identify therapeutic targets for AD dementia. This study aims to define molecular and cellular signatures of cognitive resilience, protection and resistance, by integrating genetics, bulk RNA, and single-nucleus RNA sequencing data across multiple brain regions from AD, resilient, and control individuals. Methods: We analyzed data from the Religious Order Study and the Rush Memory and Aging Project (ROSMAP), including bulk (n=631) and multi-regional single nucleus (n=48) RNA sequencing. Subjects were categorized into AD, resilient, and control based on β-amyloid and tau pathology, and cognitive status. We identified and prioritized protected cell populations using whole genome sequencing-derived genetic variants, transcriptomic profiling, and cellular composition distribution. Results: Transcriptomic results, supported by GWAS-derived polygenic risk scores, place cognitive resilience as an intermediate state in the AD continuum. Tissue-level analysis revealed 43 genes enriched in nucleic acid metabolism and signaling that were differentially expressed between AD and resilience. Only GFAP (upregulated) and KLF4 (downregulated) showed differential expression in resilience compared to controls. Cellular resilience involved reorganization of protein folding and degradation pathways, with downregulation of Hsp90 and selective upregulation of Hsp40, Hsp70, and Hsp110 families in excitatory neurons. Excitatory neuronal subpopulations in the entorhinal cortex (ATP8B1+ and MEF2Chigh) exhibited unique resilience signaling through neurotrophin (modulated by LINGO1) and angiopoietin (ANGPT2/TEK) pathways. We identified MEF2C, ATP8B1, and RELN as key markers of resilient excitatory neuronal populations, characterized by selective vulnerability in AD. Protective rare variant enrichment highlighted vulnerable populations, including somatostatin (SST) inhibitory interneurons, validated through immunofluorescence showing co-expression of rare variant associated RBFOX1 and KIF26B in SST+ neurons in the dorsolateral prefrontal cortex. The maintenance of excitatory-inhibitory balance emerges as a key characteristic of resilience. Conclusions: We identified molecular and cellular hallmarks of cognitive resilience, an intermediate state in the AD continuum. Resilience mechanisms include preservation of neuronal function, maintenance of excitatory/inhibitory balance, and activation of protective signaling pathways. Specific excitatory neuronal populations appear to play a central role in mediating cognitive resilience, while a subset of vulnerable SST interneurons likely provide compensation against AD-associated dysregulation. This study offers a framework to leverage natural protective mechanisms to mitigate neurodegeneration and preserve cognition in AD.

Download

Proteomics analysis characterizing new markers related to Aβ plaques and tau tangles pathologies

January 2025

·

10 Reads

Background Several studies have recently emerged describing relationships between cerebrospinal fluid (CSF) proteins and beta‐amyloid (Aβ) and tau pathology. While these studies have primarily characterized Alzheimer’s disease (AD) proteinopathies using CSF markers, positron emission tomography (PET) more accurately captures these pathologies, especially fibrillar tau pathology. Our objective was to identify the main proteins strongly associated with AD pathology measured by PET, and to further investigate their cellular role using postmortem transcriptomics and immunohistochemistry. Method We included 604 BioFINDER‐2 participants with CSF measurements of proteins (Olink Explore3072) at baseline, and Aβ‐PET and tau‐PET at baseline and longitudinally. We fitted linear regressions between protein levels as outcome and (1) global Aβ‐PET and temporal meta‐ROI tau‐PET SUVR or (2) their rate of change as independent variables. Enrichment analyses were performed to characterize biological processes related to the set of significant proteins. Single‐nuclei sequencing datasets were used to investigate cell‐type specificity and differential gene expression of the main proteins in relation to AD pathology. Result Analyses were restricted to 127 differentially abundant proteins that we previously identified as related to AD (manuscript in revision). ITGAM and SMOC1 showed the strongest associations with Aβ‐PET load, with SMOC1 being the only protein showing an association in Aβ‐positive participants only (Figure 1a). SMOC1 was mainly expressed in oligodendrocyte precursor cells (OPCs), and ITGAM in microglia (Figure 1b). In a large single‐nuclei human dataset, SMOC1 gene expression was increased with greater AD pathology primarily in OPCs (Figure 2), and immunohistochemistry revealed accumulation in Aβ plaques (Figure 3). Higher baseline tau‐PET and greater longitudinal change were associated with a set of 15 proteins, particularly in Aβ‐positive participants (Figure 1a). Such tau‐related proteins were mainly expressed in neurons (Figure 1b) and enriched for two terms associated with glycolysis, from which the key contributing genes were ENO1, ENO2 and GPI. In single‐nuclei sequencing data, ENO1 and ENO2 gene expression were increased with greater tau tangle pathology primarily in neurons (Figure 2). Conclusion Through comprehensive proteomics analysis of CSF proteins recently found to be associated with AD, we identified differential associations with Aβ plaques and tau tangles, and further corroborated such findings in postmortem data.


Deciphering the molecular and cellular underpinnings of cognitive resilience in Alzheimer’s disease

January 2025

·

34 Reads

Background A significant proportion of individuals preserve cognitive function despite meeting neuropathological criteria for Alzheimer’s disease (AD) at autopsy, known as cognitive resilience. We aimed to define the molecular and cellular signatures of cognitive resilience against AD. Method We integrated multi‐modal data from the Religious Order Study and Memory and Aging Project (ROSMAP), including bulk (n = 631) and multi‐regional single nucleus (n = 48) RNA sequencing. Subjects were categorized into AD, Resilient, and Control based on Aβ and tau pathologies, and cognitive status. We investigated genetic risk and transcriptomic changes in resilience and prioritized protected cell populations using genetic enrichment and cellular distribution estimation. We further characterized these populations using multiplex immunofluorescence. Result Resilient individuals exhibited an intermediate genetic risk profile between AD and Control. Remarkably, only GFAP and KLF4 were differentially expressed between Resilient and Control subjects in bulk tissue. GFAP was upregulated in Resilient astrocytes in the dorsolateral prefrontal cortex compared to AD and Control. Inhibitory and excitatory neurons displayed distinct brain region‐specific phenotypes in cognitive resilience. Somatostatin‐positive interneurons were enriched for genes linked to protective rare genetic variants and showed vulnerability in AD but not in Resilient individuals. Specific excitatory neuronal populations in the entorhinal cortex exhibited resilience‐like behavior and expressed genes previously associated with cognitive resilience. Conclusion Our findings suggest that at the bulk tissue transcriptome level, cognitive resilience does not exhibit marked gene expression differences from healthy aging, despite significant Aβ and tau neuropathology. At the cellular level, specialized excitatory neuronal populations may drive cognitive resilience, while a specific subset of interneurons may play a crucial role in other forms of protection against AD‐associated neuronal vulnerability. This systematic study provides direct insight into the molecular basis of cognitive resilience, yielding targets offering the potential to convert natural protective systems into effective therapeutic interventions for AD.



The role of cholinergic signaling in multi-sensory gamma stimulation induced perivascular clearance of amyloid

November 2024

·

28 Reads

Modulatory neurotransmitters exert powerful control over neurons and the brain vasculature. Gamma Entrainment Using Sensory Stimuli (GENUS) promotes amyloid clearance via increased perivascular cerebral spinal fluid (CSF) flux in mouse models of Alzheimer's Disease. Here we use whole-brain activity mapping to identify the cholinergic basal forebrain as a key region responding to GENUS. In line with this, GENUS promoted cortical acetylcholine release, vascular dilation, vasomotion and perivascular clearance. Inhibiting cholinergic signaling abolished the effects of GENUS, including the promotion of arterial pulsatility, periarterial CSF influx, and the reduction of cortical amyloid levels. Our findings establish cholinergic signaling as an essential component of the brain's ability to promote perivascular amyloid clearance via non-invasive sensory stimulation.



Perturbations to Stimulus-Dependent Gene Activity Patterns in Neurodegenerative Disorders

November 2024

·

21 Reads

Many of the enduring effects of experience, such as the formation of long-term memories, require the activation of new gene transcription programs in neurons immediately following the exposure to a stimulus. While disruptions in neuronal activity-dependent transcription programs manifest in neurodevelopmental disorders, emerging evidence suggests that activity-dependent transcription programs are also disrupted in progressive neurodegenerative disorders. In this chapter, we discuss how altered synapse-to-nucleus signaling dysregulates activity-dependent gene transcription programs in neurodegenerative disorders. We then present insights from epigenomic and chromatin interaction profiling studies, which reveal how stimulus-responsive gene activity states are rewired in neurodegenerative diseases and could underlie disease progression. Finally, we examine how recurrent DNA breaks at activity-dependent genes and age-related changes to DNA repair could lead to the progressive deterioration of neuronal functions.


Multisensory gamma stimulation enhances adult neurogenesis and improves cognitive function in a mouse model of Down syndrome

October 2024

·

51 Reads

Down syndrome (DS) has been linked with deficits in hippocampal dependent cognitive tasks and adult neurogenesis, yet treatment options are still very limited. We and others previously showed that a non-invasive multisensory gamma stimulation using light and sound at 40 Hz ameliorated Alzheimer’s disease pathology and symptoms in mouse models. In this study, we tested the effects of 40 Hz multisensory stimulation in the Ts65Dn mice, a mouse model of DS. For three weeks, mice were exposed daily to one hour of stimulation or one hour of ambient light and sound. Mice receiving the stimulation showed improved object recognition and spatial working memory. Using single nuclei RNA-seq and experimental validations in mouse hippocampal samples, we identified underlying expression changes in gene regulatory networks and demonstrated increased adult neurogenesis and reorganization of synapses as potential mechanisms for these improved cognitive phenotypes. Together, our data reveal a novel effect of multisensory gamma stimulation on adult neurogenesis and beneficial effects of 40 Hz treatment on cognitive function in DS model mice. Significance Statement We present strong evidence, using a well-characterized mouse model, that the cognitive and neurogenesis deficits in Down syndrome can be improved through non-invasive multi-sensory gamma stimulation. Employing a systems biology approach, we provide extensive hippocampal single-cell resolution gene expression signatures and changes in gene regulatory networks in response to sensory gamma stimulation.


Correlations between regional gene expression and PET patterns
Differentially abundant proteins for which the regional gene expression (Allen Human Brain data) was related to either the regional tau- (a) or Aβ-PET (b) SUVR deposition. Only proteins significant after accounting for spatial autocorrelation and across two brain atlases (Desikan-Kiliany and Schaefer) are displayed. The only exception is MAPT (in gray), which was only significant in one atlas. CDH6 is in red as it is the only one with a negative correlation. Correlation coefficients and significance (two-sided test, no adjustment for multiple corrections) are shown from the Desikan-Kiliany atlas. See the Supplementary material for all detailed methods and results. * corresponds to p < 0.05, ** corresponds to p < 0.01.
Aβ and tau PET association in separate models
a, b, Standardized beta coefficients from linear models relating AD fibrillar pathology at baseline (Aβ- and tau-PET SUVR included separately in different models) and over time (Aβ- and tau-PET rate of change included separately in different models) to the CSF protein levels of the 128 differentially expressed proteins. Models included age, sex, mean overall protein level as covariates. There was no significant associations with Aβ-PET rate of change, and thus those results are not displayed. Results in panel a included all CU and MCI participants. Results in panel b were restricted to Aβ-positive CU and MCI participants. All linear regressions performed were two-sided, and p-values were adjusted for false discovery rate. * corresponds to pFDR < 0.05, ** corresponds to pFDR < 0.01, *** corresponds to pFDR < 0.001 Aβ = beta-amyloid; CU = cognitively unimpaired; MCI = mild cognitive impairment.
Average gene expression levels across cell types in the Allen Brain dataset
Proportion of gene expression by cell type from single-cell transcriptomics data from the middle temporal gyrus from the differentially expressed proteins that were not included in Fig. 3b. To improve legibility, only average expression above 5% are displayed. Transcriptomics data was downloaded from the reference donors of the Allen Brain Institute.
Average gene expression levels across cell types in the ROSMAP single nuclei data
Proportion of gene expression by cell type from single-nuclei data from the dorsolateral prefrontal gyrus of 427 ROSMAP donors. The 128 DAPs are depicted on the y-axis. Average expression was calculated across the whole sample (left column for each cell type, ‘Whole’), only A− donors (middle column for each cell type, ‘Neg’) and only A+ donors (right column for each cell type, ‘Pos’). The A− or A+ status was defined based on the CERAD score (A− being No AD or Possible; A+ being Definite or Probable). Transcriptomics data was accessed from Mathys et al, Cell, 2023.
Cell-type enrichment analyses
a, b, Cell-type enrichment analyses based on single-cell transcriptomics data from the middle temporal gyrus based on the different categories of differentially expressed proteins (a) and taking all proteins part of the different biological modules (b). Bootstrap enrichment tests were performed, and all p-values were adjusted for false discovery rate. * corresponds to pFDR < 0.05, ** corresponds to pFDR < 0.01.

+9

Proteomic changes in Alzheimer’s disease associated with progressive Aβ plaque and tau tangle pathologies

August 2024

·

248 Reads

·

10 Citations

Nature Neuroscience

Proteomics can shed light on the dynamic and multifaceted alterations in neurodegenerative disorders like Alzheimer’s disease (AD). Combining radioligands measuring β-amyloid (Aβ) plaques and tau tangles with cerebrospinal fluid proteomics, we uncover molecular events mirroring different stages of AD pathology in living humans. We found 127 differentially abundant proteins (DAPs) across the AD spectrum. The strongest Aβ-related proteins were mainly expressed in glial cells and included SMOC1 and ITGAM. A dozen proteins linked to ATP metabolism and preferentially expressed in neurons were independently associated with tau tangle load and tau accumulation. Only 20% of the DAPs were also altered in other neurodegenerative diseases, underscoring AD’s distinct proteome. Two co-expression modules related, respectively, to protein metabolism and microglial immune response encompassed most DAPs, with opposing, staggered trajectories along the AD continuum. We unveil protein signatures associated with Aβ and tau proteinopathy in vivo, offering insights into complex neural responses and potential biomarkers and therapeutics targeting different disease stages.


An aging-sensitive compensatory secretory phospholipase that confers neuroprotection and cognitive resilience

August 2024

·

49 Reads

Breakdown of lipid homeostasis is thought to contribute to pathological aging, the largest risk factor for neurodegenerative disorders such as Alzheimer’s Disease (AD). Cognitive reserve theory posits a role for compensatory mechanisms in the aging brain in preserving neuronal circuit functions, staving off cognitive decline, and mitigating risk for AD. However, the identities of such mechanisms have remained elusive. A screen for hippocampal dentate granule cell (DGC) synapse loss-induced factors identified a secreted phospholipase, Pla2g2f , whose expression increases in DGCs during aging. Pla2g2f deletion in DGCs exacerbates aging-associated pathophysiological changes including synapse loss, inflammatory microglia, reactive astrogliosis, impaired neurogenesis, lipid dysregulation and hippocampal-dependent memory loss. Conversely, boosting Pla2g2f in DGCs during aging is sufficient to preserve synapses, reduce inflammatory microglia and reactive gliosis, prevent hippocampal-dependent memory impairment and modify trajectory of cognitive decline. Ex vivo, neuronal-PLA2G2F mediates intercellular signaling to decrease lipid droplet burden in microglia. Boosting Pla2g2f expression in DGCs of an aging-sensitive AD model reduces amyloid load and improves memory. Our findings implicate PLA2G2F as a compensatory neuroprotective factor that maintains lipid homeostasis to counteract aging-associated cognitive decline.


Citations (77)


... This disorder features two main pathological hallmarks: accumulation of amyloid-beta (Aβ) plaques and aggregation of tau protein in neurofibrillary tangles, which are central to synaptic dysfunction and neuronal death observed in AD patients (Pichet Binette et al., 2024). These changes lead to dementia, which affects approximately 57 million people worldwide and accounts for a substantial portion of disability in the elderly population, exceeding the impacts of stroke, cardiovascular disease and cancer (Mulligan et al., 2023). ...

Reference:

Hydroxyl chalcone derivative DK02 as a multi‐target‐directed ligand for Alzheimer's disease: A preclinical study in zebrafish
Proteomic changes in Alzheimer’s disease associated with progressive Aβ plaque and tau tangle pathologies

Nature Neuroscience

... 11 Most recently, two preclinical studies demonstrated attenuated myelin loss in response to sensory gamma stimulation in the cuprizone-and chemotherapy-induced demyelination mouse models, via mechanisms of oligodendrocyte activation and diminished neuroinflammation. 12,13 The current proteomics data also showed that most of the affected proteins belonged to the complement/acute phase AD module, consistent with the previously reported effect on cytokines and neuroinflammatory markers. 2 Neuroimmune dysfunction is a critical pathophysiological mechanism in AD, 14 Changes were observed in other proteins regulating synaptic function, synaptic plasticity, and neuronal network development, including ...

Multisensory gamma stimulation mitigates the effects of demyelination induced by cuprizone in male mice

... Also, there are still debates on methods for inferring gene coexpression from single-cell data. With methods designed to model coexpression from single-cell sparse data (Su et al. 2023; Lopez-Delisle and Delisle 2022; Wang, Choi, and Roeder 2021; Mathys et al. 2024) to others methods, such as hdWGCNA (Morabito et al. 2023) and our approach, that are based on aggregation strategies, designed to create pseudo bulk matrices and apply traditional methods originally designed for bulk RNASeq data. Similarly to our findings, most previous studies observed a large proportion of module conservation between cell types, suggesting consistent regulatory landscapes across cells (McKenzie et al. 2018;Harris et al. 2021;Morabito et al. 2023). ...

Single-cell multiregion dissection of Alzheimer’s disease

Nature

... To efficiently and accurately annotate our data, we integrated external single-nucleus RNA-seq brain datasets from various regions to create a reference atlas to label the fine-grained cell subtypes in the RNA modality using multiple references from [10,11,12,13] (Methods Section 6.4). As illustrated by the t-SNE visualizations in Fig. 1d and e, we identified nine glutamatergic excitatory neuron (Ext) types and ten GABAergic inhibitory neuron (Inh) types in both the PFC and INS. ...

Single-cell genomics and regulatory networks for 388 human brains
  • Citing Article
  • May 2024

Science

... To validate our SWR detection approach and assess the functional relevance of these events, we examined their relationship with neuronal firing (Adaikkan, 2024). We observed an increase in the Multi-unit activity (MAU) related to a high ripple band power ( Figure 1A). ...

Silencing CA1 pyramidal cells output reveals the role of feedback inhibition in hippocampal oscillations

... Ultrastructural correlates that distinguish excitatory from inhibitory synapses were identified 50 years ago [141][142][143] , while more recent work has begun to elucidate the relationship between synapse size and synaptic strength 1,2,4,115 or even ultrastructure and neurotransmitter content 144 . Conversely, new methods in expansion microscopy and multiplex super-resolution imaging can provide increasingly rich molecular information about single synapses 93,99,[111][112][113][114] , although at the expense of ultrastructural context (but see [145][146][147] ). Our direct measurement of receptor content rigorously aligned with ultrastructural features at single-synapse resolution represents an important step toward a functional interpretation of connectomes. ...

Dense, Continuous Membrane Labeling and Expansion Microscopy Visualization of Ultrastructure in Tissues

... 11 Most recently, two preclinical studies demonstrated attenuated myelin loss in response to sensory gamma stimulation in the cuprizone-and chemotherapy-induced demyelination mouse models, via mechanisms of oligodendrocyte activation and diminished neuroinflammation. 12,13 The current proteomics data also showed that most of the affected proteins belonged to the complement/acute phase AD module, consistent with the previously reported effect on cytokines and neuroinflammatory markers. 2 Neuroimmune dysfunction is a critical pathophysiological mechanism in AD, 14 Changes were observed in other proteins regulating synaptic function, synaptic plasticity, and neuronal network development, including ...

Gamma entrainment using audiovisual stimuli alleviates chemobrain pathology and cognitive impairment induced by chemotherapy in mice
  • Citing Article
  • March 2024

Science Translational Medicine

... In NDs with motor dysfunction such as PD, EE can also improve motor coordination and balance through the cotransplantation of dopaminergic neurons [46]. In some models of NDs, commonly AD and PD, EE has been demonstrated to mitigate the accumulation of pathological markers, such as β-amyloid plaques and α-synuclein [73]. EE can also promote neural regeneration and repair damaged neural tissue by activating endogenous neural stem cells [42]. ...

Multisensory gamma stimulation promotes glymphatic clearance of amyloid

Nature

... It is now widely accepted that the APOE ε4 allele is one of the strongest genetic risk factors for age-related cognitive decline and the subsequent risk of AD and related dementia (Vance et al., 2024). ...

Report of the APOE4 National Institute on Aging/Alzheimer Disease Sequencing Project Consortium Working Group: Reducing APOE4 in Carriers is a Therapeutic Goal for Alzheimer's Disease
  • Citing Article
  • January 2024

Annals of Neurology