Joseph W. Lewcock

This study investigates how TREM2 expression levels affect microglial function, metabolism, and response to TREM2 agonists in a mouse model of Alzheimer's disease.

This study shows that LRRK2 kinase activity affects BMP and GSL levels in lysosomes, linking lysosomal dysfunction to Parkinson's disease through changes in GCase activity and BMP accumulation.

This paper demonstrates that dual targeting of TfR and CD98hc enhances brain exposure of large molecules compared to single-target approaches.

This study shows that long-term anti-Aβ treatment reduces amyloid plaques and microglial activation but leaves residual plaques with persistent immune activity.

This study shows that GPR34 regulates microglia function and loss-of-function in TREM2 KO microglia rescues cholesterol metabolism, suggesting GPR34 as a therapeutic target for Alzheimer's disease.

This study investigates TfR-mediated BBB transport in mice across development and aging, finding elevated transport in early development and stability across adulthood, including in an AD model.

This study develops an antibody transport vehicle targeting the transferrin receptor to improve brain delivery of anti-amyloid antibodies, reducing ARIA-like lesions and vascular inflammation in a mouse model.

This study compares the biodistribution of Fc-engineered molecules targeting BBB receptors with standard antibodies, showing distinct CNS and peripheral organ targeting.

This study shows SARM1 causes calpain-dependent dendrite degeneration in mouse hippocampal neurons, revealing distinct degeneration pathways in axons and dendrites.

DNL343 reduces neurodegeneration in mouse models by inhibiting the integrated stress response and normalizing dysregulated biomarkers, with potential clinical relevance for vanishing white matter disease.

Peripheral AAV-mediated delivery of brain-penetrant PGRN rescues TDP-43 pathology, neurodegeneration and motor phenotypes in FTLD-GRN models.

This paper demonstrates that systemically delivered OTV, a TfR-binding molecule, effectively transports ASO across the BBB, achieving widespread and sustained knockdown of target genes in the CNS of mice and non-human primates.

The paper compares brain delivery and efficacy of two TfR-targeted enzyme fusions in MPS II mice, finding the moderate-affinity ETV:IDS has better brain exposure and substrate reduction than the high-affinity IgG:IDS.

This study shows that TREM2 deficiency reduces microglial hyperactivation in GRN-deficient models but does not rescue lysosomal dysfunction or neurodegeneration biomarkers.

This paper characterizes microglial metabolic changes in an APP knock-in mouse model of AD, finding lipid dysregulation and immunometabolic perturbations linked to fibrillar Aβ.

The paper introduces VariantKey, a reversible numerical encoding for genetic variants, and presents compounds that inhibit stress granule formation and TDP-43 accumulation in ALS/FTD models.