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Alzheimer's Association International Conference 2026

July 12-15, 2026 | London, United Kingdom, and Online

6352

Investigating The Relationship Between Endo-lysosomal Dysfunction And TDP-43 Pathology In Alzheimer’s Disease

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Poster Presenter

Jordan Ogg

Authors

Jordan Ogg, Mamatha Damodarasmy, Chizuru Kinoshita, Martin Darvas, Caitlin Latimer, Jessica Young

Affiliations

, University of Washington

Part of Topic

Investigating The Relationship Between Endo-lysosomal Dysfunction And TDP-43 Pathology In Alzheimer’s Disease

Jordan Danielle Ogg, Mamatha Damodarasamy, Chizuru Kinoshita, Martin Darvas, PhD, Caitlin Latimer, Jessica Young.
Department of Laboratory Medicine and Pathology, University of Washington, Seattle, WA, USA.

TDP-43 is a major pathology in ADNC and LATE-NC

•TAR DNA-binding protein of 43 kDa (TDP-43) is a key regulator of mRNA and gene expression3. Its pathological mislocalization and aggregation are the central pathology in many neurodegenerative diseases, including ALS, FTLD-TDP, and the majority of Alzheimer’s disease (AD) cases 4.5

•In limbic regions of the brain, TDP-43 pathology defines limbic predominant age-related encephalopathy (LATE)6,7.

•TDP-43 dysfunction disrupts RNA splicing, leading to cryptic exon inclusion4. TDP-43 has been described as having both toxic gain of function and toxic loss of function.

•While TDP-43 has been linked to several endolysosomal proteins (i.e TMEM106B), the relationship between TDP-43 and the endolysosomal network is largely unknown.

SORL1, an endolysosomal protein implicated in AD, may contribute to TDP-43 pathology

•SORL1 is an endolysosomal network (ELN) trafficking protein that binds to the retromer (containing VPS35) and is responsible for the trafficking of many AD-related proteins, such as APP, through the ELN. It has emerged as a major genetic risk factor for AD1,2

•The R953C (c2857C>T;p.Arg953Cys) SORL1 variant, recently identified in our group, results in loss of function with protein retention in the ER, enlarged early endosomes, and reduced ELN function.

•Notably, all carriers of this variant exhibit high ADNC alongside LATE, while familial non-carriers with AD lack TDP-43 pathology

•The R953C variant provides a unique opportunity to investigate ELN contributions to TDP-43 pathology and combined AD+LATE-NC.

To examine how TDP-43 may be related to SORL1 and ELN-driven changes, we (1) assess TDP-43 and ELN dysfunction in R953C variant post-mortem tissue and hIPSC-derived neurons, (2) investigate how toxic gain vs loss of TDP-43 function may contribute to ELN phenotypes

Methods: generating hiPSC-derived cortical neurons, human tissue protein isolation and FFPE immunofluorescence

Standard protocols in the Young lab for the generation of hIPSC-derived cortical neurons. After differentiation, downstream assays are used to assess protein expression and localization for TDP-43 and ELN markers. Neurons are treated with Syn hTDP-43 AAV at 1x104 vg/cell for 3 days. For lentivirus shRNA TDP-43 knock-down, neurons are treated with 1x vg/cell for 14 days (B). Pipeline to assess protein expression in human tissue after autopsy.

Results

SORL1 R953C carriers show TDP-43 pathology and reduced SORL1 immunofluorescence

hIPSC-derived neurons from R953C carriers show mislocalizedtTDP-43 and cryptic exons

TDP-43 overexpression in control neurons results in cytoplasmic TDP-43 and enlarged early endosomes

TDP-43 shRNA treatment in control cells results in decreased tTDP-43 and enlarged early endosomes

Retromer component, VPS35, as well as SORL1 may be reduced in AD+LATE human cases and TDP-43 LOF models in vitro

Conclusions and future directions

The presence of TDP-43 in the SORL1 R953C family provides a unique opportunity to investigate TDP-43 dynamics. Our findings point towards potential mechanisms of TDP-43 development in AD. Here, we show that

•SORL1 R953C tissue and hIPSC-derived cortical neurons have reduced SORL1 and increased cytoplasmic TDP-43.

•While both AAV and lentivirus experiments in control cells show enlarged early endosomes, they’re likely through different mechanisms.

•Treatment with AAV overexpression demonstrates potential toxic gain of function (cytoplasmic mislocalization, enlarged early endosomes), while lentivirus shRNA knock-down shows potential toxic loss of function (reduced VPS35, reduced SORL1, enlarged early endosomes likely due to VPS35 and SORL1 reduction).

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