Hypothesis

Chronic PERK‑ATF4 activation in pancreatic β‑cells rewires lysosomal autophagy toward unconventional secretion of oligomeric IAPP, which then seeds tau pathology in the brain; simultaneously, adipose tissue accumulates β‑amyloid in lipid droplets, acting as a peripheral sink that modulates circulating oligomer levels.

Mechanistic Rationale

PERK‑ATF4 couples ER‑stress to mitochondrial UPR and drives a metabolic shift toward glycolysis across metabolic organs [2]. Persistent ATF4 transcription up‑regulates genes involved in lysosomal biogenesis (e.g., TFEB targets) while simultaneously inhibiting autophagosome‑lysosome fusion, a phenotype observed in stressed β‑cells [1]. This imbalance favors the release of cytosolic oligomers via secretory autophagy or exosomes rather than their degradation.

Misfolded IAPP preferentially forms a structured prefibrillar intermediate in residues 20‑29 [3]. Heparan‑sulfate GAGs, which are upregulated in stressed islets, bind the N‑terminus and promote local α‑helix that accelerates β‑sheet assembly [4]. When lysosomal export is biased, these GAG‑stabilized oligomers enter the extracellular space, where they can cross‑seed tau aggregation as demonstrated in AD brain tissue [6].

Parallelly, adipocyte lipid droplets sequester β‑amyloid, a process amplified by advanced glycation end‑products [7]. By acting as a sink, adipose tissue may buffer circulating oligomers; however, lipid‑droplet overload impairs adipocyte function and releases inflammatory mediators that exacerbate ER stress in distant tissues, creating a vicious loop.

Thus, PERK‑ATF4 does not merely reflect a cell‑autonomous stress response; it orchestrates a systemic proteostatic circuit linking pancreatic β‑cell secretory pathology, neuronal tauopathy, and adipose amyloid buffering.

Testable Predictions

1. β‑cells with sustained PERK‑ATF4 signaling will secrete higher levels of oligomeric IAPP (detected by conformation‑specific antibodies) compared with controls, and this secretion will be blocked by lysosomal inhibition (e.g., chloroquine) or exosome release inhibitors (e.g., GW4869).
2. Plasma from PERK‑ATF4‑hyperactive mice will exhibit increased tau‑seeding activity in a biosensor assay, an effect attenuated by immunodepletion of IAPP oligomers.
3. Adipose‑specific overexpression of β‑amyloid will reduce circulating IAPP oligomer concentrations and delay tau pathology in cross‑seeding models, whereas adipose lipid‑droplet disruption (e.g., ATGL knockdown) will raise oligomer levels and accelerate tau aggregation.
4. Pharmacological reduction of PERK‑ATF4 (e.g., GSK2606414) in β‑cells will lower both extracellular IAPP oligomers and adipose amyloid deposition, improving systemic glucose tolerance.

Experimental Approach

• Generate β‑cell‑specific PERK‑ATF4 transgenic mice and littermate controls; measure lysosomal markers (LAMP1, cathepsin D), autophagic flux (LC3‑II/p62), and extracellular IAPP oligomers in plasma and isolated exosomes.
• Use a recombinant tau‑biosensor cell line (FRET‑based) to quantify seeding activity of plasma samples; confirm specificity with IAPP‑null plasma.
• Cross PERK‑ATF4 mice with adipocyte‑specific β‑amyloid overexpression lines; assess lipid‑droplet amyloid via Oil‑Red‑O/thioflavin‑T staining, circulating oligomer levels, and cognitive performance in Morris water maze.
• Treat cohorts with PERK inhibitor or GAG synthesis blocker (WAS‑406) to dissect contributions of PERK‑ATF4 versus GAG‑mediated IAPP aggregation.

Potential Implications

If validated, this hypothesis reframes T2D‑linked proteostasis collapse as a conduit for neurodegenerative risk via extracellular IAPP tau‑cross‑seeding, while highlighting adipose amyloid buffering as a modifiable peripheral compartment. Therapeutic strategies targeting PERK‑ATF4‑driven lysosomal export or enhancing adipose amyloid sequestration could simultaneously protect β‑cells, limit tauopathy, and improve metabolic health.