Li Gan on Acetylation Accelerates Aggregation of 3R, but Not 4R, Tau

COMMENT These findings are very intriguing. Given the importance of 3R and 4R ratios in neurodegeneration, the potential differential effects of acetylation on 3R and 4R could have important implications and warrant further exploration in cell-based studies and i

Li Gan on With Age, Microglia Pump cGAS, Revving Harmful Inflammation

COMMENT This report fits really well with our findings that activation of cGAS-STING, accelerated by tau pathology, represents a converging pathway and a promising therapeutic target for aging-associated neurodegeneration beyond AD (Udeochu et al., 2023). Besides

Li Gan on Ubiquitin Peptidase Linked to Increased Tau Pathology in Women

COMMENT The study provides a strong confirmation that the interplay between acetylation and ubiquitination modulates tau homeostasis, and it highlights the need to consider sex differences in targeting major mechanisms underlying neurodegenerative diseases quanti

Li Gan on Proteomics Highlight Alzheimer’s Changes in Matrisome, MAPK Signaling

COMMENT This study highlights the vast difference between alterations at the protein versus transcript levels, cautioning against over-reliance on transcriptomics datasets. The identification of a module (i.e., M7) that remains associated with cognitive decline a

Li Gan on Does Second X Chromosome Boost Women’s Resilience Against Alzheimer’s?

COMMENT This is a provocative and exciting study that addresses the sex-specific effects in Alzheimer’s disease, an understudied topic with important impact on both basic mechanistic and translational efforts. Here, the dissociation of the sex chromosomes and sex

Li Gan on Nitrosylation of GAPDH augments pathological tau acetylation upon exposure to amyloid-β.

COMMENT The proposed signaling cascade—Aβ1-42 induces nitrosylation of GAPDH, which activates p300-mediated tau acetylation on one hand, and inhibits SIRT1-mediated tau deacetylation on the other—provides an interesting mechanism on how Aβ might induce pathogenic

Li Gan on Lipidomic and Transcriptomic Basis of Lysosomal Dysfunction in Progranulin Deficiency.

COMMENT There are two exciting aspects of this paper. One is the finding that progranulin deficiency (full-length and granulins) leads to gene-dose alterations in lipid metabolism. The effects on lysosomal lipid processing are very compelling, and offer a brand-n

Li Gan on Inventory of Tau Modifications Hints at Undiscovered Functions

COMMENT This is a very important study and useful resource for the field. This is the first comprehensive, unbiased, quantitative mass-spectrometry analysis of tau modification under normal conditions. The study and analyses are rigorously performed, and the data

Li Gan on Distinct and non-redundant roles of microglia and myeloid subsets in mouse models of Alzheimer's disease.

COMMENT This paper by Mildner et al. showed that CCR2 localized at subsets of myeloid cells exert differential roles in plaque pathology. CCR2 localized on peripheral macrophages is required for their infiltration into AD mouse brain parenchyma after total-body i

Li Gan on The cysteine protease inhibitor, E64d, reduces brain amyloid-β and improves memory deficits in Alzheimer's disease animal models by inhibiting cathepsin B, but not BACE1, β-secretase activity.

COMMENT Aβ-lowering effects of E64d are very intriguing. However, since E64d inhibits numerous cathepsins, the mechanism by which E64d lowers Aβ remains unclear. Moreover, given the recent finding from Randy Nixon's group that inhibitors of cathepsins, inclu

Li Gan on SfN: The Old and the New—BACE and Cathepsin B Share the β-secretase Stage

COMMENT I agree that the roles of cysteine proteases in Aβ metabolism deserve in-depth investigation, and findings obtained with both genetic and pharmacological approaches should be evaluated in greater detail. In agreement with Dr. Vassar’s comments, the two in

Li Gan on Noninvasive optical imaging of cysteine protease activity using fluorescently quenched activity-based probes.

COMMENT Bogyo and colleagues developed a new generation of fluorescent quenched activity-based probes that can be used to visualize the dynamics of active proteases in whole animals. These elegant probes combine the “quenching” feature, which offers the advantage

Li Gan on Antiamyloidogenic and neuroprotective functions of cathepsin B: implications for Alzheimer's disease.

COMMENT Dr. Greg Hook commented that the Swedish mutation at the β-secretase site in hAPP may have prevented β-secretase activity of cathepsin B (CatB). We addressed this possibility in our original article (1). Primary cortical neurons from CatB–/– mice and CatB

Li Gan on Are Glia Active Participants in Neurodegenerative Disease?

COMMENT Designer Drugs to Target Inflammation in AD With this comment I'll add a component focused on microglia to this discussion. Accumulating evidence supports the role of microglia in neurodegenerative diseases. In AD, microglia activation has been assoc