Basic Science and Pathogenesis

Area of Science:

• Neuroscience
• Molecular Biology
• Genetics

Background:

• Alzheimer's disease (AD) studies indicate cognitive decline does not correlate with fibrillar amyloid-beta (Aβ) burden.
• This highlights the need to investigate other Aβ species in AD pathogenesis.

Purpose of the Study:

• To investigate the role of non-fibrillar amyloid-beta oligomers (oAβ) in cognitive decline and synaptic dysfunction in a transgenic mouse model.
• To explore potential PET imaging tracers for oAβ detection.

Main Methods:

• Created a transgenic mouse model overexpressing Dutch mutant human amyloid precursor protein (hAPP).
• Utilized learning behavior tests, immunohistochemistry (ICC), transmission electron microscopy (TEM), electrophysiology, and single-cell RNA sequencing.
• Employed A11 and FITC-cyclic peptide (FITC-CP) microscopy for oAβ detection and a novel PET tracer, Lys(64Cu/NOTA)]-CP.

Main Results:

• Dutch mice exhibited oAβ accumulation and impaired learning behavior proportional to oAβ levels.
• Presynaptic function, including post-tetanic potentiation and synaptic fatigue, was abnormal in Dutch mice.
• oAβ deposits were concentrated around mitochondria and the endoplasmic reticulum (ER), with reduced mitochondrial complex I activity and fewer mitochondria observed.

Conclusions:

• Accumulation of Dutch oAβ is linked to aging-related deficits in learning, presynaptic function, and mitochondrial integrity.
• Brain PET imaging with Lys(64Cu/NOTA)]-CP shows potential for monitoring oAβ levels in vivo, aiding in diagnosis.