TREM2 Agonists, Tremor, and TRPML1 Notes

• The top of the page is the lower continuation of a ROS/screening table. Visible cells mention Sirt3/SDHB trends emerging, details in an appendix, the next screening round scheduled for the new year after initial medicinal chemistry arrays, a Good triage flow chart, a matrix experiment with different stimuli and compounds in progress, and Jess Western studies scheduled for the week of Jan 22nd. A separate cell says further assay-suitability assessment using off-pathway antioxidant compounds is planned pending delivery from MedChemExpress/Sigma.
• Another visible cell describes a ROS assay with increased endpoint readouts using hydrogen peroxide; Amathus compounds tested in assay; data analysis ongoing; and an objective to find compounds that knock down ROS. It also notes an off-target mitochondrial ROS inhibitor received and to be tested in assay. Exact wording, dates, company spelling, and cell placement are manual-review items.
• The next visible section is TREM2 (Triggering Receptor Expressed on Myeloid Cells 2). Under Pathway normal, the table states that ligands such as oligomeric Ab, lipids, and ApoE bind TREM2, that TREM2 interacts with DAP12 in microglia, and that microglia transition from a homeostatic to a disease-associated state.
• The TREM2 pathway row shows increased or changed phagocytosis-related outputs, including amyloid beta peptide, myelin cholesterol, amyloid beta peptide and apoptotic neurons, and cytokines. Arrow direction, beta symbols, cytokine names such as IL-6/MIP-1a, and exact table alignment require manual verification.
• Under Mechanism in AD, the visible table includes an unknown ligand binding TREM2, a rare missense mutation rs75932628-T predicted to result in an R47H substitution, decreased TREM2 interaction with DAP12 in microglia, decreased transition from homeostatic to disease-associated microglia, decreased phagocytosis of amyloid beta peptide, a tau-related arrow, myelin debris/cholesterol and cholesteryl ester accumulation, decreased phagocytosis of apoptotic neurons, uncertain cytokines, and decreased soluble TREM2 in CSF. Exact arrows, symbols, and biological phrasing are high-risk.
• A heading states Genotype-phenotype correlation of TREM2, with a visible note that the low frequency of TREM2 variants makes it difficult to establish robust genotype-phenotype correlation.
• The pipeline of TREM2 agonists table includes an AL002 (Alector + AbbVie) row with mechanism TREM2 activating antibody, a P2 (INVOKE-2) stage, and a dense trial-description cell. The visible text describes a randomized, double-blind, placebo-controlled Phase 2 study in early Alzheimer’s disease, around 250 participants aged 50-85, MMSE/CDR/RBANS criteria, IV AL002 versus placebo, CDR-SB as a primary endpoint, secondary endpoints including MMSE, RBANS, ADAS-Cog13, ADCS-ADL-MCI, ADCOMS, and safety/tolerability, and a primary completion date of June 2023. Exact values, criteria, brackets, and endpoint wording need manual review.
• The same AL002 row includes source links/notes visible as ClinicalTrial.gov (October 19, 2020), Alector CTAD 2019 presentation PR, Alector AL002 publication PR, and 1st participant dosed 10130; these compact source/contact-like strings should be checked before reuse.
• A P1 row says Alector announced Phase 1 AL002 data in healthy volunteers at CTAD 2019, that AL002 was generally safe and well-tolerated, and that the data indicated target engagement in the brain as measured by cerebrospinal fluid biomarkers sTREM2 and sCSF-1R. A preclinical row says AL002c treatment was beneficial after plaque formation, suggesting anti-TREM2 antibodies may help even when introduced relatively late in disease. Exact AL002/AL002c wording and biomarker labels require manual verification.
• Additional lower rows show TREM2-activating small molecule, Denali, and ATV:TREM2, but the row contents are mostly blank or cut off on this photo.
• A Tremor section begins below. The visible comparison table has columns including Rest tremor, Postural tremor, Action or kinetic tremor, and Essential tremor. Clinical-feature cells describe postural tremor as occurring during maintenance of a position against gravity and increasing with action, and action/kinetic tremor as occurring during voluntary movement.
• The Essential tremor cell lists onset at any age but most common in people age 40 and older, body parts typically in hands and usually beginning in the hands first, prognosis worsening over time, comparison versus PD as worsening with movement while PD is resting tremor, and cause including 50%: genetic mutation (autosomal dominant): 'familial tremor'. Exact bullets and punctuation need manual verification.
• A pathophysiology row for essential tremor says ET involves the cerebellum and connected brainstem areas, where imaging and postmortem studies have shown Purkinje cell loss and other histological abnormalities, probably leading to oscillatory activity in the cerebellothalamocortical circuit. Citation numbers are visible but high-risk.
• The bottom of the page begins a TRPML1 section. Visible text states that TRPML1 is encoded by mucolipin-1 (MCOLN1), localized in late endosomes, and contains a lipase domain between S1 and S2 segments. It mentions MCOLN1/MTORC1 activity, HEK293T cells, thapsigargin, Ca2+-permeable channels TRPM3 and MCOLN1, basal autophagy bypassing MTOR through CAMKK2-AMPK, MCOLN1 activation of CAMKK2 and AMPK in ARPE-19 cells, PtdIns3P, class III PtdIns3K, PPP3/calcineurin, TFEB, autophagy, and lysosomal biogenesis.
• A red therapeutic-strategy line is visible: Tx strategy: TRPML1 activation -> lysosomal Ca2+ release -> (calcineurin-dependent) TFEB nuclear translocation -> autophagy, lysosomal biogenesis with upward-arrow styling in the image. The exact arrow symbols and final phrase should be manually checked.
• A Korean note says the channel is also a lysosomal iron-trafficking channel (lysosomal iron-trafficking channel이기도 함. (Misko)). Adjacent text describes TRPML1 channels as proton leak channels in lysosomes and notes MCOLN1 as a characterized lysosomal Ca2+-release channel activated by stimuli such as starvation during autophagy. The section continues off the bottom edge.

block	visible structure
ROS/screening continuation	Upper multi-column table continuation with dates, screening plans, assay-suitability notes, matrix experiment, ROS assay, and mitochondrial ROS inhibitor note
TREM2 pathway normal	Compact table with ligand binding, DAP12 interaction, microglia-state transition, and phagocytosis/cytokine outputs
TREM2 mechanism in AD	Wide mechanistic table with rare TREM2 mutation, DAP12/microglia-state changes, phagocytosis, tau, CE accumulation, apoptotic neurons, cytokines, and soluble TREM2 in CSF
TREM2 agonist pipeline	Dense drug/program table with AL002, mechanism, phase/stage, clinical-trial details, PR/source notes, P1 and preclinical rows, and sparse TREM2 small-molecule rows
Tremor	Comparison table for rest, postural, action/kinetic, and essential tremor, with clinical features and pathophysiology
TRPML1	Lower text section with MCOLN1/TRPML1 biology, MTORC1/autophagy mechanisms, red therapeutic-strategy line, Korean note, and continuation below the photo

Exact table-cell wording, source strings, dates, program names, contacts/URLs, trial criteria, endpoint labels, citations, arrows, beta/Ca2+ symbols, Korean notes, figure references, and lower continuation text require manual image verification before KB reuse.

Uncertain Spans

• Dense tables, diagrams, arrows, and small labels may not be captured reliably by OCR.
• IDs, dates, trial criteria, endpoint names, stage labels, source strings, contacts/URLs, mutation names, cytokines, citation numbers, Greek letters, Ca2+ notation, beta symbols, and Korean notes require manual image verification.
• The upper ROS/screening table is a continuation from an adjacent photo; compare neighboring photos before interpreting dates or row meanings.
• The TREM2 agonist pipeline table is dense and tilted; use body tiles and adjacent evidence for exact transcription.
• The Tremor table and TRPML1 section both continue beyond the visible page crop and should be compared with adjacent photos.
• Navigation pane active item Symptom is useful context but should not be treated as the page title.