The age‑dependent loss of calbindin diminishes neuronal calcium buffering, leaving cytosolic Ca2+ to rise after synaptic activity [1]. This prolonged elevation activates calpain, generating toxic protein fragments that overwhelm the ubiquitin‑proteasome and autophagy systems [2,3]. We propose that, when canonical buffers fail, the proteome redirects misfolded proteins into amorphous or ordered aggregates that serve as secondary calcium sinks. Acidic side chains exposed on the surface of tau, amyloid‑β, and α‑synuclein aggregates can bind Ca2+ with low‑affinity, high‑capacity kinetics, thereby lowering free cytosolic Ca2+ and attenuating calpain activation. This repurposing converts aggregation from a mere waste product into a homeostatic mechanism that sequesters both damaged polypeptides and excess ions—a functional analogue of calbindin’s EF‑hand buffering.

Support for this view comes from the biphasic effect of calcium on proteostasis: modest Ca2+ spikes enhance HSF‑1‑driven chaperone expression [4], whereas sustained elevation drives a 15‑fold increase in pathogenic aggregation [5]. The EPS‑8/RAC pathway, which destabilizes actin to seed aggregates, is itself calcium‑sensitive [6]; thus, rising Ca2+ not only promotes seed formation but also creates the very structures that can thereafter bind the ion. Crucially, interventions that restore calcium homeostasis improve clearance pathways [7] and caloric restriction preserves calbindin levels [8], suggesting that the cell actively modulates the balance between endogenous buffers and aggregate‑based sinks.

If aggregates act as calcium buffers, their dissolution should exacerbate Ca2+‑dependent toxicity even when total protein load is unchanged. A testable prediction: neurons expressing aggregation‑prone tau mutants that lack surface acidic residues (e.g., tau‑ΔE/D) will show normal aggregate formation but fail to buffer Ca2+, resulting in heightened calpain activity and faster degeneration compared with wild‑type tau‑expressing cells under identical calcium stress. Conversely, chemically inducing aggregate formation with a non‑toxic, acidic‑rich peptide should rescue calcium buffering in calbindin‑knockdown neurons, reducing calpain cleavage and preserving viability. These experiments can be performed in primary hippocampal cultures using Fluo‑4 Ca2+ imaging, Western blotting for calpain‑spectrin breakdown products, and live‑cell death assays. In vivo, AAV‑mediated expression of acidic‑rich aggregate‑promoting peptides in calbindin‑heterozygous mice should attenuate age‑dependent calcium dysregulation and slow tangle‑like pathology, whereas immunotherapy‑mediated aggregate clearance would worsen calcium metrics and cognitive performance.

This hypothesis reframes therapeutic strategies: rather than indiscriminately dismantling aggregates, we might modulate their calcium‑binding capacity or bolster endogenous buffers to maintain the protective sink until healthier proteostasis can be re‑established. It also explains why some aggregates correlate with neuroprotection (e.g., early‑stage, soluble oligomers that efficiently bind Ca2+) while others predict neurodegeneration (large, dense plaques that sequester Ca2+ ineffectively and impede diffusion). Direct measurement of aggregate‑bound calcium using genetically encoded Ca2+ indicators targeted to the aggregate interior will provide a definitive test of the buffer function.