Targets for Amyloidosis

Amyloidosis is a heterogeneous group of disorders characterized by the misfolding, aggregation, and extracellular deposition of amyloid fibrils derived from various precursor proteins. Understanding the molecular targets directly involved in amyloidogenesis is critical for elucidating disease mechanisms, identifying diagnostic biomarkers, and developing targeted therapies. The directly relevant targets—amyloid beta precursor protein (APP), beta-2-microglobulin (B2M), transthyretin (TTR), and leukocyte cell derived chemotaxin 2 (LECT2)—represent the major amyloidogenic proteins implicated in different forms of amyloidosis (e.g., Alzheimer's disease, dialysis-related amyloidosis, hereditary and wild-type transthyretin amyloidosis, and LECT2 amyloidosis). These proteins are central to disease onset and progression, as their misfolding and aggregation drive tissue damage and organ dysfunction. By focusing on these targets, research can delineate pathogenic pathways, enable rational drug design (e.g., stabilizers, aggregation inhibitors, silencing therapies), and support clinical development of disease-modifying interventions. Categorizing targets by their mechanistic involvement provides a framework for understanding disease heterogeneity and guides personalized therapeutic strategies.

Amyloidogenic Precursor Proteins

This category comprises proteins whose abnormal folding, aggregation, and deposition are directly responsible for the formation of amyloid fibrils in various types of amyloidosis. The major targets in this group—Amyloid Beta Precursor Protein (APP), Transthyretin (TTR), Beta-2-Microglobulin (B2M), and Leukocyte Cell Derived Chemotaxin 2 (LECT2)—are each associated with a distinct clinical subtype of amyloidosis. Their structural instability, post-translational modifications, and proteolytic processing are central to disease pathogenesis. Interventions targeting these proteins (e.g., small molecule stabilizers, gene silencing, aggregation inhibitors) have shown clinical promise, and quantification of their misfolded forms serves as a biomarker for disease diagnosis and progression monitoring.

Amyloid Beta Precursor Protein (APP)

Amyloid Beta Precursor Protein (APP) is a type I transmembrane glycoprotein with a large extracellular domain, a single transmembrane region, and a short cytoplasmic tail. Key domains include the E1 and E2 domains (extracellular), the Aβ region (residues 672–713 in APP770 isoform), and the YENPTY motif in the C-terminus. APP undergoes complex proteolytic processing via the amyloidogenic (β- and γ-secretase) and non-amyloidogenic (α- and γ-secretase) pathways. In the amyloidogenic pathway, sequential cleavage by BACE1 (β-secretase) and γ-secretase releases amyloid-β (Aβ) peptides, notably Aβ1-40 and Aβ1-42, which aggregate into neurotoxic oligomers and fibrils. APP mutations, overexpression, or altered processing increase Aβ production and are causative in familial Alzheimer's disease (AD). Aβ accumulation triggers synaptic dysfunction, neuroinflammation, and neuronal loss. APP is regulated by phosphorylation, trafficking, and interaction with adaptor proteins. Therapeutic strategies include β/γ-secretase inhibitors, anti-Aβ antibodies, and gene silencing. APP and its cleavage products are established biomarkers in AD clinical trials. (Entrez: 351 [human], 11820 [mouse]; KEGG: 351, 11820; UniProt: P05067 [human], P12023 [mouse]).

Transthyretin (TTR)

Transthyretin (TTR) is a homotetrameric protein predominantly produced in the liver and choroid plexus, with a β-sheet-rich structure forming a central channel for thyroxine and retinol-binding protein transport. Each monomer has 127 amino acids with a core β-barrel domain. TTR amyloidosis arises from destabilization of the tetramer, leading to monomer dissociation, misfolding, and aggregation into amyloid fibrils. Over 140 pathogenic TTR mutations (e.g., V30M, V122I) increase amyloidogenic propensity, causing familial amyloid polyneuropathy (FAP) and familial amyloid cardiomyopathy (FAC), while wild-type TTR aggregates cause senile systemic amyloidosis. TTR stability is regulated by small molecule binding (e.g., tafamidis, diflunisal), post-translational modifications, and proteolysis. Evidence from genetic, biochemical, and clinical studies supports a direct pathogenic role; TTR deposits are diagnostic for TTR amyloidosis. Therapeutics include kinetic stabilizers, gene silencers (e.g., patisiran, inotersen), and fibril disruptors. TTR levels and mutations are established biomarkers. (Entrez: 7276 [human], 24856 [mouse]; KEGG: 7276, 24856; UniProt: P02766 [human], P02767 [mouse]).

Beta-2-Microglobulin (B2M)

Beta-2-Microglobulin (B2M) is a 99-residue, β-sandwich structured protein forming the light chain of MHC class I molecules. It is freely filtered by the kidney and catabolized in the proximal tubule. In patients with chronic renal failure on long-term hemodialysis, B2M accumulates in plasma, leading to its misfolding and aggregation into amyloid fibrils, particularly in osteoarticular tissues (dialysis-related amyloidosis, DRA). The molecular mechanism involves conformational destabilization at acidic pH and post-translational modifications (e.g., truncation, oxidation). B2M amyloid binds to collagen and glycosaminoglycans, facilitating tissue deposition. Clinical and histopathological studies confirm its direct role as the amyloidogenic protein in DRA. B2M levels serve as a biomarker for DRA risk. Therapeutic approaches focus on high-flux dialysis, β2-microglobulin adsorption, and stabilization strategies. (Entrez: 567; KEGG: 567; UniProt: P61769).

Leukocyte Cell Derived Chemotaxin 2 (LECT2)

Leukocyte Cell Derived Chemotaxin 2 (LECT2) is a 16-kDa secreted protein with a β-sheet-rich fold, produced mainly in the liver. LECT2 amyloidosis (ALECT2) is a recently recognized form of systemic amyloidosis, most commonly affecting the kidney and liver. The precise molecular mechanism is not fully elucidated, but LECT2 aggregation is thought to involve conformational instability and aberrant proteolytic processing. No pathogenic mutations have been consistently identified, suggesting that overproduction or impaired clearance may contribute. LECT2 amyloid deposits are Congo red positive and immunoreactive for LECT2. Clinical evidence supports a direct pathogenic role, with LECT2 immunohistochemistry serving as a diagnostic marker. There are currently no targeted therapies; management is supportive. (Entrez: 3950; KEGG: 3950; UniProt: O14960).