Alzheimer's Disease Preclinical Biomarkers

Phfr, Inc.

Alzheimer's Disease

Preclinical Biomarkers for Alzheimer's Disease


Molecular Schematic of Αβ Peptide Aggregation
 in Alzheimer's Disease Senile Plaque Formation

Molecular Modeling of GPC Binding to Αβ(1-28) 

Micro-imaging H217O Proton Signal

The brain levels of glycerophosphocholine (GPC), a membrane phospholipid breakdown product, go up with normal aging with a further two- to three-fold increase above normal aging in AD (Pettegrew et al., 1984; 1987; 1988a,b; 1994; 1995a; 2000a; 2001).

GPC enhances the in vitro aggregation of Aβ(1-40) 4-fold over control conditions (Klunk et al., 1997).

GPC is shown to bind to a peptide fragment of Aβ(1-40), forming a pocket comprised of three amino acids - namely Lys28, Asp23, and Lys16 (GPC Binding) (McClure et al., 2001).  GPC binding to these three sites causes Aβ(1-40) to undergo a conformational change to a conformation that contains a β-turn in the vicinity of amino acid residues 25-30; the β-turn enhances Aβ(1-40) aggregation (Aβ Aggregation).

A search of the protein data bank of 11,996 structures revealed that only Aβ peptide contained the three-center site for optimal GPC binding.  Further studies by 2D-NMR techniques confirm the binding of GPC to Aβ(1-40) at the same binding site (Mandal and Pettegrew, 2004) resulting in an α-helical to β-sheet conformational change in Aβ(1-40).

 GPC enters the brain after oral administration (Abbiati et al., 1993).

GPC contains 6 oxygen atoms in which the highly abundant 16O (99.76%) can be replaced with the low abundance 17O (0.037%).  17O will quench the MRI signals of any surrounding protons (Arai et al., 1989; Kwong et al., 1991; Charagundla et al., 2000).  This will appear as a dark spot on an MRI image which we have demonstrated (Micro-Imaging).  Using computer technology the dark spot can be converted into a semi-quantitative color image.

17O GPC will be an extremely valuable non-invasive in vivo biomarker for the initial (earliest) molecular changes in Aβ(1-40) conformation which culminates in the deposition of Aβ(1-40) in senile plaques in AD brain.

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