1. Background of Technology
1.1. Amyloid hypothesis in Alzheimer's disease
- Clinical association of amyloid42 oligomers with Alzheimer's disease
: Detection of amyloid42 oligomers in the brain of AD patients
: Apparent evidence for the role of amyloid42 oligomer in AD Pathology
: High ratio of Amyloid 42/40 for pathology
1.2. Amyloid42 receptors: not successful yet
- RAGE (Nature 1996)
: Role in amyloid transport in BBB (2008, 2009, ICAD)
: However, a role in the memory impairment of AD is not clear
- ABAD (Science 2005)
: Role in mitochondria for amyloid toxicity
: However, a role of ABAD in the memory impairment of AD is not clear
-Prion (Nature 2009) etc.
: Role in LPT
: However, a role in the memory impairment of AD is not clear yet.
1.3. Limited available targets in the amyloid pathology for drug development in AD
- Beta, gamma secretases are good targets but development of inhibitors have problems.
: Gamma-secretase: too many substrates
: Beta secretase: Difficulty to design inhibitor in brain
-Aggregation blockers, amyloid antibody etc.
: Long history, being tried by many groups.
1,4. Looking for New therapeutic targets
-Additional new targets are needed.
2. Description on Technology Applied
2.1. Amyloid 42-binding receptor (AIMP) discovered
-Interaction was confirmed in in vitro and cell level
-Amyloid42-selective interaction (Amyloid40 not bound))
-Monomer and oligomeric forms of amyloid42 bind to AIMP receptor
-Binding region was identified by in silico modeling and by mutagenesis
2.2. Role of the amyloid receptor in amyloid pathogenesis
-Increased expression of AIMP in the brains of AD and APP moce
-Essential role of AIMP receptor in neurotoxicity and Tau phosphorylation in cultured neuronal cells
-Inhibition of amyloid42-induced memory impairment in AIMP receptor KO mice (icv injection)
-No reduction in amyloid42-induced LTP in the brain of AIMP receptor KO mice.
-AIMP KO/PDAPP double transgenic mice rescue memory impairment of PDAPP mice.
-There is another ligand for the receptor and thus, selective inhibition is required to avoid unwanted effects.
2.3. Small compound inhibitor (inhibitor X) against amyloid receptor:
-AIMP inhibitor compound Isolated from in silico modeling
: Using in silico-modeling of the receptor and amyoid42, one million compounds were screened.
- In vitro, in vivo effects: Inhibition of receptor-mediated memory impairments
: AIMP inhibitor inhibits the interaction of amyloid42 with AIMP
: AIMP inhibitor inhibits amyloid42-induced neuronal toxicity in vitro
: AIMP inhibitor inhibits amyloid42-induced memory impairment (memory test after amyloid42 i.c.v. injection).
: AIMP plays a role in neuronal transport of amyloid42
: Being tested for BBB transport.
Taken together, these in vitro and in vivo analysis of AIMP and its inhibitor provide a proof of concept that AIMP may serve as a receptor of amyloid42 (Fig. 1)