The TREM2/DAP12 signaling pathway normally functions as a critical gatekeeper preventing trans-synaptic tau propagation through specialized microglial surveillance at synaptic clefts. TREM2 receptors on microglial processes positioned at tripartite synapses detect extracellular tau oligomers released from presynaptic terminals through direct binding to tau's microtubule-binding domain. Upon tau detection, TREM2-DAP12 activation triggers rapid Syk-mediated phosphorylation cascades that mobilize microglial engulfment machinery specifically targeting tau-containing synaptic vesicles and dendritic spines. This process involves CX3CR1-mediated microglial positioning and complement receptor CR3 activation for synaptic material phagocytosis. When TREM2 function is compromised by pathogenic variants (R47H, R62H), the surveillance system fails, allowing tau oligomers to accumulate in synaptic clefts where they bind to postsynaptic NMDA and AMPA receptors. This tau-receptor interaction facilitates tau internalization through clathrin-mediated endocytosis and subsequent retrograde transport via dynein motors along microtubules to the soma.
...Curated pathway from expert analysis
graph TD
A["MAPT gene<br/>expression"]
B["Tau protein<br/>production"]
C["Hyperphosphorylated<br/>tau accumulation"]
D["Locus coeruleus<br/>neurons"]
E["Microtubule<br/>destabilization"]
F["Axonal transport<br/>impairment"]
G["Norepinephrine<br/>release reduction"]
H["Hippocampal<br/>noradrenergic<br/>denervation"]
I["Synaptic plasticity<br/>dysfunction"]
J["Neuroinflammation<br/>activation"]
K["Cellular stress<br/>response failure"]
L["Hippocampal tau<br/>pathology spread"]
M["Memory and<br/>cognitive decline"]
N["Noradrenergic<br/>replacement therapy"]
O["Tau aggregation<br/>inhibitors"]
A -->|"transcription"| B
B -->|"pathological<br/>modification"| C
C -->|"selective<br/>vulnerability"| D
D -->|"tau toxicity"| E
E -->|"transport<br/>disruption"| F
F -->|"neurotransmitter<br/>depletion"| G
G -->|"circuit<br/>disconnection"| H
H -->|"loss of<br/>modulation"| I
H -->|"reduced<br/>anti-inflammatory"| J
H -->|"impaired<br/>neuroprotection"| K
I -->|"functional<br/>decline"| M
J -->|"tissue<br/>damage"| L
K -->|"vulnerability<br/>increase"| L
L -->|"progressive<br/>pathology"| M
N -->|"circuit<br/>restoration"| H
O -->|"tau<br/>reduction"| C
classDef normal fill:#4fc3f7,color:#0d0d1a
classDef therapeutic fill:#81c784,color:#0d0d1a
classDef pathology fill:#ef5350,color:#0d0d1a
classDef outcome fill:#ffd54f,color:#0d0d1a
classDef molecular fill:#ce93d8,color:#0d0d1a
class A,B,D,G molecular
class E,F,I,K normal
class C,H,J,L pathology
class M outcome
class N,O therapeuticMedian TPM across 13 brain regions for TREM2 from GTEx v10.
No curated ClinVar variants loaded for this hypothesis.
Run scripts/backfill_clinvar_variants.py to fetch P/LP/VUS variants.
No DepMap CRISPR Chronos data found for TREM2.
Run python3 scripts/backfill_hypothesis_depmap.py to populate.
No resource usage or linked notebooks recorded for this hypothesis yet.