Visualization of amyloid β deposits in the human brain with matrix-assisted laser desorption/ionization imaging mass spectrometry

Abstract

The neuropathology of Alzheimer’s disease (AD) is characterized by the accumulation and aggregation of amyloid β (Aβ) peptides into extracellular plaques of the brain. The Aβ peptides, composed of 40 amino acids, are generated from amyloid precursor proteins (APP) by β- and ?-secretases. Aβ is deposited not only in cerebral parenchyma but also in leptomeningeal and cerebral vessel walls, known as cerebral amyloid angiopathy (CAA). While a variety of Aβ peptides were identified, the detailed production and distribution of individual Aβ peptides in pathological tissues of AD and CAA have not been fully addressed. Here, we develop a protocol of matrix-assisted laser desorption/ionization-based imaging mass spectrometry (MALDI-IMS) on human autopsy brain tissues to obtain comprehensive protein mapping. For this purpose, human cortical specimens were obtained from the Brain Bank at the Tokyo Metropolitan Institute of Gerontology. Frozen cryosections are cut and transferred to indium-tin-oxide (ITO)-coated glass slides. Spectra are acquired using the MALDI system with a spatial resolution up to 20 µm. Sinapinic acid (SA) is uniformly deposited on the slide using either an automatic or a manual sprayer. With the current technical advantages of MALDIIMS, a typical data set of various Aβ species within the same sections of human autopsied brains can be obtained without specific probes. Furthermore, high-resolution (20 µm) imaging of an AD brain and severe CAA sample clearly shows that Aβ1-36 to Aβ1-41 were deposited into leptomeningeal vessels, while Aβ1-42 and Aβ1-43 were deposited in cerebral parenchyma as senile plaque (SP). It is feasible to adopt MALDIIMS as a standard approach in combination with clinical, genetic, and pathological observations in understanding the pathology of AD, CAA, and other neurological diseases based on the current strategy.