Alzheimer's Imaging Consortium

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.
• Non-fibrillar Aβ species are increasingly implicated in AD pathogenesis.

Purpose of the Study:

• To investigate the impact of Dutch mutant human amyloid precursor protein (hAPP) overexpression on cognitive function, synaptic plasticity, and mitochondrial health in a transgenic mouse model.
• To characterize the accumulation and distribution of oligomeric Aβ (oAβ) in the brain and its correlation with behavioral deficits.

Main Methods:

• Created transgenic mice overexpressing Dutch mutant hAPP (APPE693Q) under a pan-neuronal Thy1 promoter.
• Utilized behavioral testing, immunohistochemistry (ICC), transmission electron microscopy (TEM), electrophysiology, and single-cell RNA sequencing.
• Employed A11 and FITC-cyclic peptide (FITC-CP) fluorescence microscopy for oAβ detection and PET imaging with Lys(64Cu/NOTA)]-CP.

Main Results:

• Dutch mice exhibited impaired learning behavior proportional to brain oAβ levels, with accumulation of non-fibrillar oAβ and alpha-CTFs but not Aβ fibrils.
• Electrophysiological studies revealed abnormal presynaptic function, including impaired post-tetanic potentiation and synaptic fatigue.
• Single-cell RNA-seq identified altered transcriptional profiles in excitatory neurons, associated with protein translation and oxidative phosphorylation defects, and reduced mitochondrial complex I activity.

Conclusions:

• Accumulation of Dutch oAβ is linked to age-related deficits in learning, presynaptic function, and mitochondrial structure and function.
• Brain PET imaging using novel tracers may offer a method for monitoring oAβ levels and distribution in living subjects for AD diagnosis.