Molecular basis of amyloid imaging

Makoto Higuchi

Molecular Imaging Center, National Institute of Radiological Sciences

Accumulation of amyloidogenic components exemplified by amyloid β peptide (Aβ) and hyperphosphorylated tau proteins has been implicated in Alzheimer's disease (AD) as one of the critical events in the activation of a pathogenic molecular network leading to the symptomatic manifestation. Visualization of amyloid fibrils by in-vivo imaging techniques accordingly offers diagnostic information at a prodromal stage of the disease, and facilitates therapeutic evaluations during the course of emerging anti-amyloid treatments. By comparing findings in positron emission tomographic (PET) amyloid imaging of AD and model mouse brains, an N-terminally cleaved and modified Aβ termed Aβ_N3（pE） has been identified as a major constituent of “AD-like” Aβ plaques enriched with binding sites for imaging agents. The deposition of Aβ_N3（pE） is conceived to be mechanistically linked to characteristics of the Aβ processing and its alterations in aging and AD, highlighting the role of Aβ_N3（pE） in the aging-mild cognitive impairment-AD continuum. This insight also provides potential approaches to the regulation of the Aβ metabolism aimed at reducing Aβ_N3（pE） , therapeutic effects of which is assessable by using PET probes preferentially binding to the Aβ_N3（pE） amyloid. Thus, clarification of the molecular pathogenesis and development of diagnostic and therapeutic agents can synergistically promote each other with the aid of molecular imaging technologies. Meanwhile, PET observations demonstrate that the Aβ_N3（pE） fibrillogenesis may not immediately trigger neurodegenerative insults, and additional pathologies — putatively tau lesions — are supposed to be required for the onset of neurotoxicity. In this context, detection of tau inclusions in living brains would be of vital significance, and structural considerations on β-sheet ligands open an avenue to the selective mapping of Aβ and tau amyloids. Near-simultaneous imaging of these hallmark lesions and other elements such as activated microglia and impaired neurotransmissions, which form a mutually connected network in the pathogenesis of AD, would help revisiting the importance of therapeutically targeting amyloid depositions toward deactivation of this network.

Address correspondence to Dr. Makoto Higuchi, Molecular Imaging Center, National Institute of Radiological Sciences (4-9-1 Anagawa, Inage-ku, Chiba, Chiba 263-8555, Japan)