T1WI-SWI Dual Modal Magnetic Resonance Nanoprobes for Accurate Diagnosis of Early Stage Alzheimer's Disease.

Beta-site APP-cleaving enzyme 1 (BACE1), a critical rate-limiting enzyme that synthesizes β-amyloid peptide (Aβ), is an important marker of early pathological changes in Alzheimer's disease (AD). Early small plaques cannot be accurately detected using traditional Magnetic resonance imaging (MRI) probes. Therefore, magnetic resonance tuning (MRET) and susceptibility weighted imaging (SWI)-based smart responsive MR nanoprobes are designed to achieve the sensitive detection of BACE1 and Aβ plaques. This probe is modified with a blood-brain barrier-penetrating targeting peptide that enables its reach to the AD microenvironment. The enhancement of T1WI signals owing to the MRET effect caused by the separation of probes in response to BACE1 is used to reflect real-time BACE1 changes. When Aβ plaques are present, the remaining probes that bound around Aβ plaques underwent in situ thiol cross-linking under the action of peroxynitrite (ONOO-) in the AD microenvironment, and SWI can magnify magnetic susceptibility differences, which significantly increased the Aβ plaque detection sensitivity. This probe combines the advantages of T1WI and SWI and can simultaneously visualize and reflect the BACE1 level and Aβ plaque distribution. This approach overcomes the limitations of traditional single-target probes and provides a new noninvasive and highly accurate strategy for the early diagnosis of AD.