Abstract
β <math><mrow><mi>β</mi></mrow> </math> -Amyloid ( A β <math><mrow><mi>A</mi> <mi>β</mi></mrow> </math> ) plaque, representing the progressive accumulation of the protein that mainly consists of A β <math><mrow><mi>A</mi> <mi>β</mi></mrow> </math> , is one of the prominent pathological hallmarks of Alzheimer's disease (AD). Label-free imaging of A β <math><mrow><mi>A</mi> <mi>β</mi></mrow> </math> plaques holds the potential to be a histological examination tool for diagnosing AD. We applied label-free multiphoton microscopy to identify extracellular A β <math><mrow><mi>A</mi> <mi>β</mi></mrow> </math> plaque as well as intracellular A β <math><mrow><mi>A</mi> <mi>β</mi></mrow> </math> accumulation for the first time from AD mouse models. We showed that a two-photon-excited fluorescence signal is a sensitive optical marker for revealing the spatial-temporal progression and the surrounding morphological changes of A β <math><mrow><mi>A</mi> <mi>β</mi></mrow> </math> deposition, which demonstrated that both extracellular and intracellular A β <math><mrow><mi>A</mi> <mi>β</mi></mrow> </math> accumulations play an important role in the progression of AD. Moreover, combined with a custom-developed image-processing program, we established a rapid method to visualize different degrees of A β <math><mrow><mi>A</mi> <mi>β</mi></mrow> </math> deposition by color coding. These results provide an approach for investigating pathophysiology of AD that can complement traditional biomedical procedures.