About

Sally A. Frautschy is a Professor-in-Residence in the Departments of Neurology and Medicine at UCLA. Her research focuses on neurodegeneration, neuroinflammation, and the pathogenesis of Alzheimer's disease. She has contributed significantly to understanding the role of metabolic and vascular factors in tau pathology, as well as developing interventions such as curcumin and dietary modifications to mitigate neurodegenerative processes. Her work includes evaluating small-molecule disassemblers of pathological tau fibrils, investigating metabolic deficits in Alzheimer's models, and exploring neuroinflammatory mechanisms. Dr. Frautschy's research also encompasses the development of imaging techniques for amyloid pathology and the study of neurovascular interactions in dementia. Her extensive publication record and ongoing projects underscore her leadership in advancing the understanding and potential treatment strategies for neurodegenerative diseases.

Research topics

• Computer Science
• Medicine
• Chemistry
• Internal medicine
• Artificial Intelligence
• Psychology
• Ophthalmology
• Neuroscience
• Biochemistry
• Biology
• Pathology
• Chromatography
• Immunology

Selected publications

• In Vitro and In Vivo Evaluation of Small-Molecule Disassemblers of Pathological Tau Fibrils

  ACS Chemical Neuroscience · 2026-01-05 · 2 citations

  article

  Aggregation of the microtubule-binding protein tau is the histopathological hallmark of Alzheimer's disease (AD) and other neurodegenerative diseases, which are collectively known as tauopathies. Tau aggregation in AD patients is correlated with neuron loss, brain atrophy, and cognitive decline, and pro-aggregation tau mutations are sufficient to cause neurodegeneration and dementia in humans and tauopathy model mice. Thus, reversing tau aggregation is a potential therapeutic avenue for AD. In a previous study, we discovered CNS-11, a small molecule that disaggregates AD patient brain-extracted tau fibrils in vitro. In this study, we identify two chemical analogs of CNS-11, named CNS-11D and CNS-11G, that disaggregate AD patient brain-extracted tau fibrils and prevent seeding in a tau aggregation cell culture model. We also demonstrate that 8 weeks of treatment with either CNS-11D or CNS-11G reduces levels of insoluble tau in a mouse model of tauopathy. Our work defines the properties of two small molecules that diminish aggregation of tau in vivo and provides further support for structure-based methods to target tau for treatment of AD.

  PublisherDOI

• Early emergence of motivational and hedonic feeding deficits in the TgF344-AD rat model of Alzheimer’s disease

  Frontiers in Aging Neuroscience · 2025-04-28 · 6 citations

  articleOpen access

  Introduction: Alzheimer's disease (AD) is characterized by progressive cognitive decline and has a long prodromal phase during which subclinical cognitive deficits and neuropsychiatric symptoms may begin to emerge. Apathy, defined as a lack of motivation or volition, is increasingly recognized as a core feature and a potentially early marker of AD. Despite its significance, apathy-like behavior has been underexplored in transgenic models of AD. Methods: We performed a longitudinal analysis of apathy-like behavior using the well-established TgF344-AD rat model. We compared male and female TgF344-AD and wildtype rats on hedonic (palatable food intake) and motivational (progressive ratio) assays during early (3-4 months), intermediate (6-7 months), and later (9-10 months) stages of adulthood. Results: We found that female TgF344-AD rats exhibited early and persistent deficits in motivational and hedonic feeding, emerging at 3-4 months and 6-7 months, respectively. During a battery of cognitive tests conducted after 12-14 months of age, TgF344-AD rats were impaired in spatial working memory but also showed wide-ranging deficits in exploratory behavior, which may also be indicative of an apathy-like loss of investigatory drive. Conclusion: Our findings highlight the TgF344-AD rat as a valuable model for studying early apathy-like behavior in AD and underscore the need to consider sex differences in AD research to better understand the prodromal phase of this disease.

  PublisherOA PDFDOI

• CNS-11g reduces α-synuclein pathology and restores motor function in a Parkinson’s model

  Research Square · 2025-11-13

  preprintOpen access1st authorCorresponding
  PublisherOA PDFDOI

• Covid‐19 Spike protein impact on Alzheimer's (AD) and Cerebrovascular Disease

  Alzheimer s & Dementia · 2025-12-01

  articleOpen access1st authorCorresponding

  BACKGROUND: Most COVID-19 cases fully recover, but 7% report persistent symptoms (Long Covid, LC). SARS-CoV2 uses surface S1 Spike protein to bind ACE2 receptors leading to sustained complement activation. S1 activates endothelial C3, leukocyte attachment and invasion, also observed in atherosclerosis, cerebral amyloid angiopathy (CAA), and hypertension-driven small vessel disease (CSVD). LC patients have elevated plasma AD biomarkers and postmortem evidence of microglial, complement and microvascular pathology. AD patients are at increased risk for Neuro-Covid particularly those with ApoE4 and hypertension. Here we explore modulatory roles of hypertension or ApoE4 on the response to S1 in AD rats. METHOD: We created rat models with AD or mixed AD (AD with CSVD) with or without ApoE4. Outcomes included executive function, AD pathology, white matter damage and complement activation 6 weeks after subcutaneous injection of recombinant S1. We developed high throughput plasma assays to assess vascular and CNS complement activation from rat models or human Neuro-Covid. RESULT: Experiment 1: Independent of human ApoE or hypertension, S1 increased plaque and vascular amyloid and amyloid responsive ptau217, microvascular active C3 (C3d) and neuronal and vascular complement C5b-9 terminal attack complex. E4 and hypertension synergized to increase vascular pathology induced by spike. This was accompanied by leukocyte adhesion, including neutrophils. Experiment 2: S1 spike injected 11-13 month rats showed spike-induced executive function deficits and significant increases in the hypertensive FAD rats for beta amyloidogenic APP BACE processing, ptau217 as well as loss of myelin basic protein, an index of white matter damage. We also observed increased cortical active C3, CSF C5a (ELISA), and active C3 in plasma endothelial and astrocyte-derived EV. Pre-existing hypertensive comorbidity potentiated Covid spike effects. The plasma of LC patients with Neuro-Covid showed elevated active C3 in astrocyte and endothelial EV. CONCLUSION: Spike protein caused robust increases in AD pathology as well as persistent pathogenic CNS and vascular complement activation, associated with synapse loss and BBB damage in rats with pre-existing AD and vascular pathology, a situation found in at least 20 to 30% of our aged population. Scalable assays for Neuro-Covid complement activation should facilitate treatment.

  PublisherOA PDFDOI

• Harnessing cGAS-STING signaling to counteract the genotoxic-immune nexus in tauopathy

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-09-28 · 2 citations

  preprintOpen access

  Tauopathies are progressive neurodegenerative disorders characterized by aberrant tau aggregation, cognitive decline, and persistent neuroinflammation, yet the mechanisms driving neuroinflammation and disease progression remain incompletely understood. Here, utilizing human postmortem AD brains and a mouse model of tauopathy, we report that genotoxic stress-induced cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) immune pathway form a self-amplifying loop that fuels neuropathology and cognitive deficits. Targeted disruption of this cycle through either genetic deletion of cGAS or pharmacological inhibition of STING restores immune homeostasis and attenuates tau pathology and cognitive deficits. Our results showed a significant accumulation of DNA double-strand breaks (DDSBs) and impaired DNA repair function, alongside elevated cGAS-STING signaling and type I interferon (IFN-I) responses in human AD brains compared to non-AD. In the PS19 transgenic (PS19Tg) mouse model of tauopathy, we found significantly elevated levels of DDSBs and altered expression of DNA repair proteins during early stages of disease, which preceded the dysregulation of cGAS-STING signaling and emergence of significant neuropathology in the later stage. Interestingly, genetic deletion of cGAS shifted microglial polarization from a pro-inflammatory M1 phenotype toward an anti-inflammatory M2 state, accompanied by a reduction in IFN-I signaling and improved cognitive performance in PS19Tg mice. Pharmacological STING inhibition reshaped the transcriptomic landscape, revealing selective regulation of pathways governing synaptic plasticity, and immune responses. This transcriptional reprogramming was accompanied by suppression of inflammatory responses, reduction in synaptic pathology, and attenuation of tau pathology in PS19Tg mice, underscoring STING as a therapeutic target for tauopathy. In conclusion, our findings reveal that genotoxic-immune crosstalk drives neuroinflammation and tau pathology and identify a conserved, druggable cGAS-STING axis that can be targeted to impede or slow disease progression in tauopathies.

  PublisherOA PDFDOI

• Efficacy of a synuclein and tau fibril targeting drug in vivo

  Alzheimer s & Dementia · 2025-12-01

  articleOpen accessSenior author

  BACKGROUND: Pre-Fibrillar oligomeric and insoluble fibrillar aggregates of alpha-synuclein (aSyn) accumulate and contribute to the neurodegenerative decline in Parkinson Disease (PD) and other synucleinopathies and frequently occur as co-morbidities in the major tauopathy, Alzheimer Disease (AD). Familial autosomal dominant PD aSyn A53T mutations which promote aggregation cause age-related aSyn and tau pre-fibrillar oligomers and insoluble aSyn fibrillar deposits, neurodegeneration and motor deficits in hemizygous A53T aSyn transgenic mice. METHOD: To test a candidate fibril structure-based therapeutic candidate we treated aSyn deposit-bearing 24 month old heterozygous A53T M83 mice for 6 weeks with a formulation of CNS11g, a small molecule designed to specifically fit an aSyn fibril site required for aggregation and previously demonstrated to disaggregate both pre-existing aSyn and tau fibrils in cell free systems. RESULT: Oral gavage produced brain levels above the in vitro ED50 for disaggregation and ameliorated motor deficits with no evidence of toxicity compared with the vehicle group. CNS11g reduced levels of putatively neurotoxic, SDS-stable, high molecular weight soluble aSyn aggregates detected above 256kD by Western blot analysis in spinal cord and brainstem as well as tau oligomers in spinal cord. Quantitative ICC for p129S aSyn deposits and reactive glia, supported a significant treatment effect, but there was no effect on detergent insoluble p129S aSyn. Our late intervention results provide evidence for effective oral CNS11g delivery, safety and efficacy in reducing motor deficits and soluble p129S aSyn and tau oligomers and aSyn deposits by ICC without biochemical evidence for reducing pre-existing insoluble fibrillar aSyn deposits with this treatment paradigm. CONCLUSION: While higher or longer dosing might disaggregate and clear insoluble fibrils, this initial study suggests oral dosing produces pleiotropic CNS activity against both aSyn and tau pre-fibrillar oligomers implicated in the neurotoxicity, seeding and spreading of two major proteinopathies.

  PublisherOA PDFDOI

• Disruption of electrophysiological rhythms and memory impairment in an Alzheimer’s transgenic rat model

  Alzheimer s Research & Therapy · 2025-09-01 · 2 citations

  articleOpen access

  BACKGROUND: Alzheimer's disease (AD) is one of the most prevalent causes of dementia, characterized by progressive memory loss and cognitive decline. Abnormal electrophysiological patterns, especially interictal epileptiform discharges (IEDs) and high-frequency oscillations (HFOs), have been observed in mouse models of AD and are suggested to contribute to cognitive dysfunction. However, comprehensive evaluations of IEDs across different brain regions are limited, and their impact on cognitive performance and neuropathology remains unclear, particularly in more complex AD models with relevant comorbidities. To address this gap, our study aims to clarify how IEDs and HFOs contribute to cognitive decline and neuropathology in AD, potentially informing the development of new biomarkers for early detection. METHODS: We investigate these effects in an AD (PS1/APP) rat model (FAD+) with coexisting hypertension-associated small vessel disease (SVD), as well as in their transgene-negative littermates (FAD-). We conducted behavioral experiments at 6, 8, and 11 months of animal age, alongside neural signal recordings at 8 and 11 months. AD pathology (neuritic plaques and hyperphosphorylated tau) and novel biomarkers (14-3-3γ) or biomarkers common to both disorders (neuropeptide Y, astrocyte and microglia) were evaluated at the end of the experiment. RESULTS: Seizures were observed in three out of 14 FAD + rats. IED rates were significantly greater in FAD + rats compared to FAD- at all tested periods, correlating with changes in neuropathological biomarkers. Furthermore, coupling strength between IEDs and HFOs was significantly elevated in FAD + rats, especially during the later stages of disease progression. In addition, FAD + rats exhibited deficits in both learning and recall abilities at both ages, which correlated most strongly with increased IED-HFO coupling strength. No such correlation was observed in the FAD- group. CONCLUSION: Our findings suggest that pathological synchronization between IEDs and HFOs in the hippocampus, along with neuropathological changes in both the hippocampus and entorhinal cortex, may contribute to memory dysfunction in AD, highlighting a potential mechanistic link between epileptiform activity, AD biomarker changes, and cognitive decline.

  PublisherOA PDFDOI

• ¹³ C tracing in synaptosomes reveals that SGLT2 inhibition with dapagliflozin prevents metabolic deficits in the 5X-FAD model of Alzheimer’s Disease

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-05-03 · 1 citations

  preprintOpen access

  ABSTRACT Metabolic dysfunction is linked to several forms of age-related neurodegeneration including Alzheimer’s Disease (AD), and targeting brain energy metabolism is an increasingly attractive mode of therapeutic intervention. However, commonly used in vitro methods to identify specific metabolic pathways of interest in preclinical models of neurodegenerative disease have considerable limitations. They are prone to subselection of sample material, unable to identify cell type-specific effects, or cannot identify metabolic defects upstream of mitochondria. Here we address these challenges by validating a method for stable isotope tracing with isolated synaptic nerve terminals, or ‘synaptosomes’. We further applied this approach to study glucose metabolism in synaptosomes isolated from the 5X-FAD mouse model of AD treated with the antidiabetic sodium-glucose linked transporter-2 (SGLT-2) inhibitor Dapagliflozin. Treatment with Dapagliflozin preserved steady-state levels of synaptosomal metabolites and enrichment from labeled glucose into citrate that was reduced in the 5X-FAD model. These changes correlated with trends towards improved spatial working memory but not amyloid burden. The results highlight the utility of stable isotope tracing in synaptosomes to identify precise sites of metabolic dysfunction and mechanisms of action for metabolic drug candidates in preclinical models of neurodegeneration.

  PublisherOA PDFDOI

• Liganded magnetic nanoparticles for magnetic resonance imaging of α-synuclein

  npj Parkinson s Disease · 2025-04-23 · 1 citations

  articleOpen access

  Aggregation of the protein α-synuclein (α-syn) is the histopathological hallmark of neurodegenerative diseases such as Parkinson's disease (PD), dementia with Lewy bodies (DLB), and multiple system atrophy (MSA), which are collectively known as synucleinopathies. Currently, patients with synucleinopathies are diagnosed by physical examination and medical history, often at advanced stages of disease. Because synucleinopathies are associated with α-syn aggregates, and α-syn aggregation often precedes onset of symptoms, detecting α-syn aggregates would be a valuable early diagnostic for patients with synucleinopathies. Here, we design a liganded magnetic nanoparticle (LMNP) functionalized with an α-syn-targeting peptide to be used as a magnetic resonance imaging (MRI)-based biomarker for α-syn. Our LMNPs bind to aggregates of α-syn in vitro, cross the blood-brain barrier in mice with mannitol adjuvant, and can be used as an MRI contrast agent to distinguish mice with α-synucleinopathy from age-matched, wild-type control mice in vivo. These results provide evidence for the potential of magnetic nanoparticles that target α-syn for diagnosis of synucleinopathies.

  PublisherOA PDFDOI

• Phenomics Study Reveals Predictable Converging Molecular Signatures in CTE, Alzheimer's and Models of Mild TBI

  Alzheimer s & Dementia · 2025-12-01

  articleOpen access

  BACKGROUND: Traumatic brain injury (TBI) accelerates risk for multiple Alzheimer's Disease and Related Dementias (ADRDs) featuring Tau protein hyperphosphorylation and tauopathy. Mild TBI (mTBI) causes a temporary disruption of brain function typically caused by blast, blow, or jolt to the head. While many individuals recover fully within a few weeks or months, some may experience long-term cognitive deficits, but how TBI progresses to ADRDs including tauopathies remains complex and elusive. The present study identified the combinations of risk genes and timing of mTBI induced by open-field blasts (OFB) that alter candidate fluid and imaging biomarkers involved, so that making early intervention possible to prevent or delay the progression of ADRD. METHOD: human wild-type Tau/CamKII bitransgenic (rT1) and Non-carrier/non-carrier mice were assigned randomly into two groups: OFB-induced repetitive mTBI and sham control and evaluated for transgene and TBI-dependent behavioral deficits at 3 months post-injury. The brain tissues were collected for proteomics studies using high-resolution label-free global and phospho-proteomics by liquid chromatography coupled with tandem mass spectrometry, followed by A.I. informed phenomic analysis integrating behavioral-related proteomic datasets with human databases. Immunoblotting validated selected phenomics findings. RESULT: We identified co-expression subnetworks that were strongly correlated with PTSD-like behavioral endophenotypes in humans including psychomotor agitation, fear response, and physical activity in rT1 mice following OFB-induced repetitive mTBI. Biologically-informed neural networks (BINN)-enhanced eXplainable Artificial Intelligence (XAI) analysis of the differential expression (DE) profiles in human ADRD cohorts that differentiate symptomatic CTE and AD from asymptomatic AD and age-matched human controls, identified overlapping networks in both mouse and human studies. Key proteins that regulate synaptic vesicle cycling, synaptic plasticity, and energy metabolism displayed DE in rT1 mice as a function of tau transgene and TBI interactions and drivers to accelerate their trajectory towards ADRD. Several of the TBI-triggered DE proteins (YWHAG or 14-3-3 γ, HNRNPA2B1, and hexokinase), overlapped reported phosphoTau and Tau oligomer interactomes with proposed causal roles in metabolic deficits and neurodegeneration. CONCLUSION: This study unveiled ADRD predictable converging molecular signatures that appear to drive the Tau-TBI interaction conferring both chronic neuropsychiatric impairments and neurodegenerative disease progression, shedding light on the complex etiology of ADRD.

  PublisherOA PDFDOI

Recent grants

• NIH Grant RC1AG035878

  NIH · $1.0M · 2012

• NIH Grant R01NS030195

  NIH · $374k · 1997

• NIH Grant I01RX000669

  NIH · 2016

• Neuroinflammation and Neurodegeneration in a Transgenic Alzheimer Rat with Vascular Disease

  NIH · 2017–2022

• NIH Grant R01AG010685

  NIH · $1.9M · 2006

Frequent coauthors

• Greg M. Cole

  University of California, Los Angeles

  298 shared

• Fusheng Yang

  145 shared

• Bruce Teter

  123 shared

• Gregory M. Cole

  University of California, Los Angeles

  116 shared

• Qiu‐Lan Ma

  University of Southern California

  110 shared

• Oliver J. Ubeda

  Geriatric Research Education and Clinical Center

  81 shared

• Giselle P. Lim

  University of California, Los Angeles

  76 shared

• Mychica Jones

  VA Greater Los Angeles Healthcare System

  55 shared

Education

• M.D., Neurology

  University of California, Los Angeles

  1980

• B.A., Psychology

  University of California, Los Angeles

  1976