Alzheimer's disease (AD), known as the most common form of dementia, is an age-related neurodegenerative disorder, which contributes to 60-70% of dementia cases. Although the abnormal accumulation of lipids was noted in the early studies of AD neuropathology, it is only in recent decades that lipid metabolism has become a growing focus. Especially, the challenges faced in clinical trials targeting the two main AD hallmarks - amyloid plaques and neurofibrillary tangles - have pushed for a further comprehensive understanding of the role of lipid homeostasis in AD pathogenesis.

The use of micro-spectroscopic imaging methods enables an ex vivo screening of molecular signatures in AD-tauopathy mouse brains in a label-free manner. Specifically, this study employs a suite of vibrational micro-spectroscopic techniques, such as Fourier transform infrared (FTIR) spectroscopic imaging, synchrotron radiation-infrared (SR-IR) microscopy, Raman and stimulated Raman scattering (SRS) microscopy, and optical-photothermal infrared (O-PTIR) microscopy with multivariate data analysis, to investigate the content and distribution of proteins and lipids in the mouse hippocampus. We observed strikingly distinct morphology and biochemistry between transgenic and control mouse brain tissues. Notably, there is a significantly higher lipid content in the transgenic samples, and lipid deposits were found to overlap with activated microglia to some degree, as confirmed by the correlative SRS and two-photon fluorescence imaging. These findings lead to a better understanding of lipid dysfunction in the context of AD pathogenesis.

Reflection on the Journey. This study originated from an interdisciplinary collaboration between the groups of Prof Francesca Palombo and Dr Francesco Tamagnini, building on previous studies of mouse brain tissues with amyloidopathy using FTIR spectroscopic imaging, Raman and Brillouin micro-spectroscopy. Then the study was extended to the other main hallmark of Alzheimer’s disease, neurofibrillary tangles, using the Tg4510 mouse model. Initially, FTIR, SR-IR, and Raman imaging were employed to identify tangles in the CA1 region of the mouse brain hippocampus. Dr Jessica Mansfield kindly assisted with SRS measurements as a part of a Master's degree project by Alicia Elliot (Natural Sciences). Notably, SRS imaging, owing to its high sensitivity to lipid signals, revealed significant molecular differences between transgenic and control samples, particularly elevated lipid levels in the transgenic mice. After Alicia completed her MSci project, we completed the SRS measurements, integrated other spectroscopic methods, and validated the results with fluorescence imaging. In addition to the lipid signatures identified in the tauopathy mouse brain, we are currently investigating neurofibrillary tangles using high-resolution O-PTIR imaging.

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