Hypothesis

Progressive loss of lamin B1 in aging neurons creates a chronic, low‑efficiency signal that marks those cells for microglial clearance, analogous to developmental pruning.

Mechanistic Basis

• Lamin B1 depletion weakens the nuclear envelope, increasing basal cGAS‑STING activation and releasing cytosolic DNA–HMGB1 complexes [3]
• These DAMPs are secreted or displayed on the neuronal surface, where they are recognized by microglial TREM2 and complement receptors, priming phagocytosis.
• Simultaneously, lamin B1 loss disrupts nucleocytoplasmic transport of activity‑dependent mRNAs (e.g., Arc, BDNF), lowering synaptic firing and reducing the "eat‑me" counter‑signal CD47 [4]
• The net effect is an increased "eat‑me" / decreased "don’t‑eat‑me" ratio, converting lamin‑driven stress into an active eviction cue.

Testable Predictions

1. Neurons with lamin B1 knock‑down will show elevated surface HMGB1 and reduced CD47, and will be engulfed more frequently by microglia in vitro.
2. Pharmacological inhibition of cGAS or STING will block microglial engulfment of lamin‑deficient neurons without altering overall lamin levels.
3. Overexpressing lamin B1 in aged mice will decrease microglial neuronal contacts and preserve cortical thickness despite age‑related lamin decline.
4. Microglia lacking TREM2 will fail to clear lamin‑deficient neurons, leading to accumulation of electrophysiologically inactive cells.

Potential Experiments

• Use Cre‑dependent shRNA against Lmnb1 in excitatory neurons of young adult mice; assess microglial phagocytosis via CD68‑colocalized neuronal fragments at 1, 3, 6 months.
• Treat cultures with cGAS inhibitor RU.521 or STING antagonist C‑176; quantify engulfment by live‑cell imaging.
• Inject AAV‑Lmnb1 into the hippocampus of 18‑month mice; measure neuronal density, lamin B1 levels, and microglial activation markers (Iba1, CD68).
• Cross Lmnb1‑heterozygous mice with Trem2‑KO; evaluate neuronal survival and behavioral cognition.

If these experiments show that blocking the proposed DAMP‑microglial axis prevents neuronal loss despite lamin deterioration, the hypothesis is supported; if neuronal loss proceeds unchanged, the eviction model is falsified.