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Small Molecule Guided Small Molecule Guided Photocatalytic Proteomics Profiling of Amyloid Deposits in Hippocampal and Cortical Alzheimer’s Disease TissuesPhotocatalytic Proteomics Profiling of Amyloid Deposits in Hippocampal and Cortical Alzheimer’s Disease Tissues

ABSTRACT: he spatiotemporal progression of amyloid pathology in Alzheimer's disease (AD) follows a characteristic pattern, spreading from the cortex to the hippocampus brain regions. However, analytical methods for comparative profiling of amyloid plaque composition between these two regions are limited. Herein, we developed a small molecule guided method to selectively label, enrich, profile and compare amyloid interactome in cortical and hippocampal regions of AD brain tissue. We embarked on rational design of probes to transform Congo Red derivatives from amyloid chromophore to singlet fluorescent sensor, and finally to triplet photocatalytic labeling probe. While retaining the amyloid binding selectivity, P5 outperformed other probes in photocatalytic labeling of recombinant amyloid proteins and amyloid deposits from AD mouse brain tissues. We applied P5 to selectively labeling and enrichment of amyloid plaques in hippocampus and cortex, respectively. The robustness of our methodology was confirmed by the consistent identification of established AD biomarkers (e.g. APP, ApoE) in both regions. Subsequent comparative proteomics not only demonstrated the critical involvement of the mitophagy-lysosome axis in AD pathogenesis, but also uncovered a previously unrecognized region-specific functional divergence. Proteomic profiles distinguished that AD’s cortex primarily involves upstream mitophagy, whereas AD’s hippocampus actively triggers downstream lysosomal degradation. Overall, we report a small-molecule-based photocatalytic proteomic profiling method to resolve amyloid deposits and elucidate their region-specific interactome heterogeneity.

INSTRUMENT(S):

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Brain

SUBMITTER: Jing Yan

LAB HEAD: Jing Yan

PROVIDER: PXD075747 | Pride | 2026-03-18

REPOSITORIES: Pride

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			Action	DRS
	Results.rar	Other
	XB09826DA_cortex_J_Slot2-14_1_37314.d.rar	Other
	XB09826DA_cortex_K_Slot2-14_1_37315.d.rar	Other
	XB09826DA_cortex_L_Slot2-14_1_37313.d.rar	Other
	XB09826DA_cortex_V_Slot2-13_1_37310.d.rar	Other

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Project description:Alzheimer’s disease (AD) is a chronic ageing related neurodegenerative disease which is characterized by loss of synapses and neurons in the vulnerable brain regions. Expression perturbations of amyloid β (Aβ) and tau protein in the brain are two hallmarks of AD. Aβ is abnormally generated from amyloid precursor protein (APP) which is broadly distributed in different brain regions including the hippocampus and cortex. It is believed that increased Aβ expression plays a causative role in the early stage of AD pathology. Aβ protein interacts with the signaling pathways that control the phosphorylation of the microtubule-associated protein tau, which eventually disrupts the neuronal circuitry as well as network connectivity leading to neurodegenerative processes observed in AD. In addition, substantial molecular and neurodegenerative changes occur in the initial stage of AD even before the cognitive symptoms are evident, which makes the early diagnosis of AD vital to any timely disease stabilization and treatment. However, despite myriad efforts and substantial progress in the field to decipher the molecular mechanisms of disease onset and its progression, specific causes underlying AD pathology remain ill-defined. There is an urgent need to identify novel mechanism based interventional approaches that can stop, or slow down, the progression of AD. Therefore, it is important to improve the knowledge of the early AD and have a better understanding of the underlying molecular mechanisms induced by Aβ. In this study, we performed comparative quantitative proteomics on different brain regions of 2.5 months old APP/PS1 mice (hippocampus, frontal cortex, parietal cortex and cerebellum) in order to investigate the early stage impact of AD. Although over 5000 proteins were identified in all regions, the proteome response across regions was greatly varied. As expected, the greatest proteome perturbation was detected in the hippocampus and frontal cortex (AD-susceptible brain regions), compared to only 155 changed proteins in the cerebellum (less vulnerable region to AD). Increased expression of APP protein was identified in all brain regions. The expression of the majority of the other proteins between hippocampus and cortex areas was not similar, highlighting differential effects of the disease on different brain regions. A series of AD associated markers and pathways were identified as overexpressed in the hippocampus including glutamatergic synapse, GABAergic synapse, retrograde endocannabinoid signaling, long-term potentiation, and calcium signaling. In contrast, the expression of same proteins and pathways was negatively regulated in frontal and parietal cortex regions. Additionally, an increased expression of proteins associated with the oxidative phosphorylation pathway in hippocampus was not evident in the two cortices. Interestingly, an increased expression of proteins involved with myelination, neurofilament cytoskeleton organization, and glutathione metabolism was identified in cortex areas, while these were reduced in the hippocampus. The results obtained from this study highlight important information on brain region specific protein expression changes occurring in the early stages of AD.

Dataset Information

Small Molecule Guided Small Molecule Guided Photocatalytic Proteomics Profiling of Amyloid Deposits in Hippocampal and Cortical Alzheimer’s Disease TissuesPhotocatalytic Proteomics Profiling of Amyloid Deposits in Hippocampal and Cortical Alzheimer’s Disease Tissues

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