Proteomic and Phosphoproteomic Characterization of Disease-Associated Alterations in Nerve Terminals and Protein Inclusions of Alzheimer's Disease Patients.

Novel cell markers with altered expression in brain aging and Alzheimer's disease: A review

Aging and Alzheimer's disease are complex processes marked by continuous neuronal loss, disrupted neural networks, and cognitive decline. The past decade has seen advances in genomics, proteomics, and single-cell RNA sequencing, enabling the discovery of cellular markers with distinct gene expression patterns. This review aims to compile recent markers of aging and Alzheimer’s disease in immune, glial, and neuronal cells, which are increasingly vital for enhancing diagnostic precision and monitoring disease progression. Markers such as Triggering receptor expressed on myeloid cells 2 (TREM2) and Cluster of differentiation 33 (CD33) facilitate immune responses and function as indicators of neuroinflammation and amyloid-beta clearance; Glial fibrillary acidic protein (GFAP) and aquaporin-4 serve as indicators of gliosis and impaired interstitial fluid drainage; Postsynaptic density protein 95 (PSD-95), Synaptosomal-associated protein 25 (SNAP25), and aberrant tau phosphorylation signify synaptic degradation and cytoskeletal instability characteristic of Alzheimer's pathology. The breakdown of the blood-brain barrier is associated with endothelial nitric oxide synthase (eNOS) and vascular cell adhesion molecule 1 (VCAM-1). The markers were identified using cutting-edge technologies that unveiled variations in gene expression across cell types, brain regions, and disease stages. This cellular heterogeneity improves understanding of Alzheimer's disease (AD) progression and brain aging, clarifies molecular pathways, and may be used for prognostic and diagnostic purposes after thorough validation. Novel cellular markers with altered expression profiles are still being identified through ongoing research, which could be crucial for improving our understanding of and ability to treat neurodegenerative diseases.

Tau dysfunction in alzheimer’s disease: molecular and cellular mechanisms, genetic modulation, and therapeutic perspectives

Distinct Transcriptional States of TDP-43 Pathology in an Alzheimer's Disease Mouse Model.

A transcriptional framework linking early TDP-43 stress responses to pathological aggregation in AD is provided, and potential upstream therapeutic targets are revealed, including ERK1/2, PI3K, small GTPases, and mRNA splicing pathways.

Signaling cascades of microtubule-associated protein Tau in Alzheimer's disease.

Plaque-associated oligodendrocyte proteostatic failure underlies myelin loss in Alzheimer’s disease

Alzheimer’s disease (AD) features amyloid-β plaques and tau pathology, yet the mechanism underlying early and clinically significant myelin loss remains unresolved. Here, we report human iPSC-derived forebrain organoids with doxycycline-inducible expression of SOX10, OLIG2, and NKX6-2 (SON), which generate robust, mature oligodendrocytes and compact myelin in vitro and in vivo. Introducing amyloid precursor protein (APP) pathogenic mutations produces extracellular amyloid-β plaques and phosphorylated tau, accompanied by reduced myelin basic protein (MBP) expression and disrupted myelin ultrastructure. Single-cell and spatial transcriptomics combined with amyloid plaque imaging reveal that oligodendrocytes in plaque-dense regions show pathological changes in calcium signaling, immune activation, lipid remodeling, and protein catabolic pathways. Notably, MBP protein is reduced despite elevated myelin-related transcription, suggesting plaque-induced degradation of myelin proteins. Consistent with this, proteasomal inhibition restores MBP protein levels and improves compact myelin ultrastructure in AD organoids. In human AD brain tissue, protein catabolic pathways are similarly upregulated with increasing plaque density. Together, these findings identify plaque-associated oligodendrocyte proteostatic failure as a candidate mechanism of myelin loss and a potential therapeutic pathway in AD.

Corpora amylacea profiling reveals disease stage and brain region-specific alterations in glycogen metabolism in Alzheimer’s disease patient brains

Summary Increasing evidence indicates that shifts in brain polysaccharide metabolism can influence the progression of multiple neurodegenerative diseases. Here, we profile corpora amylacea (CA) in 230 postmortem human brains, revealing significantly higher densities in Alzheimer’s disease (AD) patients when compared with patients with other or no neurodegenerative diseases and a tight correlation of CA density with neurofibrillary tangle (NFT) pathology. Immunohistochemical profiling using an anti-glycogen antibody confirms the polysaccharide nature of CA and reveals plaque-like glycogen patches (GPs) and densely aggregated intraneuronal glycogen in AD patient brains correlated with the emergence of NFT pathology. matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI-MSI) orthogonally verifies the polysaccharide identity of these structures and that GPs can be consistently observed at early neuropathological disease stages. GPs are also observed in murine models of AD-like pathology, correlating with tau pathology. The identification of these AD-associated glycogen pathologies in the human brain implies that alterations in glycogen metabolism are tightly associated with AD pathogenesis.