Amyloid hypothesis through the lens of A? supersaturation

Deposition of aggregated amyloid-? (A?) protein in the form amyloid plaques is a pathological hallmark Alzheimer’s disease. According to hypothesis, A? aggregation initiates pathogenic cascade, eventually leading dementia. Being prevailing theory for disease, hypothesis has been used guide basic research and therapeutic interventions. Supersaturation phenomenon that occurs when concentration solute solution exceeds its thermodynamic solubility. In brain, proteins are usually supersaturated. follows principle supersaturation (So et al., 2016). this perspective, I discuss biochemical implications framework how knowledge can be improve development Main concepts context aggregation: The well described studies crystallization, which, like aggregation, exhibits nucleation-dependent polymerization kinetics (Coquerel, 2014). Through series excellent work, Goto colleagues 2016) have demonstrated also applies aggregation. Figure 1A depicts phase diagram A?. solubility curve divides undersaturated region supersaturated region. area consists metastable zone nucleation zone. boundary between corresponds “critical concentration” mentioned previous (Hellstrand 2010). zone, does not spontaneously nucleate aggregate. However, pre-formed fibrils seed spontaneous with rate dependent on concentration.Figure 1: aggregation.(A) A supersaturation. Both environmental factors affect diagram. aggregate but presence seeds. rates correlated concentrations. (B) Changes soluble as result Aggregation starts from ends at limit determined by conditions factors. A?: Amyloid-? protein.Unseeded vitro Once starts, it cannot stopped before reaches limit. Therefore, saturated represent beginning end points sigmoidal (Figure 1B). This point illustrated an elegant study Linse 2010), which shows takes place only increased approximately 200 nM. completion, represents A?, approaches around 15 under experimental Hellstrand al. (2010), range 15–200 How achieved?In vivo, achieved because produced one molecule time, allowing exceed without contrast, typically manipulating such lowering temperature or adding additives changes protein. computational analysis propensity whole proteome found substantial fraction supersaturated, particularly involved neurodegeneration-related pathways (Ciryam 2013). amyloids leads two fundamental behavior First, dominant process seeded (Cohen Second, no longer maintain deposition consequences: (1) becomes cumulative problem existing catalyze newly daily basis; (2) stuck higher than undersaturation clearance solubilization plaques. plaque-free mice, acute inhibition ?-secretase activity led rapid decline A?42concentration. plaque-rich mice showed significantly less reduction, supporting role reservoir (Hong 2011). After injecting isotopically-labeled into interstitial fluid, same 2011) recovered 45% notion most deposits Furthermore, permanently reduce A?42 concentrations several folds, they fluctuations part circadian rhythm. Bateman (Huang 2012) studied dynamics amplitude amyloid-negative group 15.6 pM, almost 3-fold amyloid-positive (6.3 pM). lowered diminished rhythm over long period time (years decades) may contribute cognitive reduced fluctuation underlie sleep disturbances observed individuals (Wang Holtzman, 2020). What tell us about brain? Based supersaturation, course person’s adult lifetime divided four phases: phase, burst reduction stationary 2). starts. steady-state. Mild impairment dementia appear years decades (Hadjichrysanthou person, increases modestly always remains Studies performed compare show markedly lower 2012; Palmqvist prediction based requires accelerated increase concentration, “burst,” so crosses 1A, moving up along Y-axis). vivo environments modulate boundaries zones even right X-axis).Figure 2: supersaturation.Two hypothetical persons considered here: (blue line) other (purple line). person slow linear never goes For phases. there differences persons. acceleration increase. As result, gradually loses ability spread through extracellular space brain. will remain largely unchanged remainder life time. Cognitive take phase. protein.What interventions? Anti-amyloid therapy advanced majority anti-amyloid drug candidates antibodies targeting amyloid. Aducanumab Biogen/Eisai (Sevigny 2016), monoclonal antibody fibrils, highly promising results 3 clinical trials disease-modifying treatment. addition potential toxicity directly themselves, basis, generate toxic species. though plaque load direct effect plaques, complete elimination after vast cleared restored state. Modulation monomeric concentration: Lowering strategy. using inhibitors modulators BACE1 ?-secretase. Alternatively, bind levels. Recent reviewed elsewhere (Long 2019). standalone strategy, approach likely effective 2), poses greatest risk initiating formation. formed, mechanism shifts plays lesser role. inhibitors: Due difference types needed. One type works best inhibit another Spontaneous important significant amount built up. mechanism, specifically screened purpose should used. Toxicity blockers: Proteins small molecules species serve blockers. class would throughout It helpful combination therapy, itself eliminate drugs elusive due lack understanding both structures Personalized biomarkers: Measurements human cerebrospinal fluid wide Although groups distinguished cutoff A?42concentration, large number individuals, example, 8% cases (2014), do agreement imaging. inter-individual A?42concentrations. establish personalized biomarker. Then compared past levels individual. shown cohorts differ 2–3 fold change magnitude readily detected individual’s history concentration. personal useful detecting if intervention removed aggregates. work was supported National Institute Health, USA (No. R01AG050687).