Neurochemical Characterization of PSA-NCAM + Cells in the Human Brain and Phenotypic Quantification in Alzheimer’s Disease Entorhinal Cortex

ABSTRACTAlzheimer’s disease (AD) is characterized by the selective vulnerability of specific neuronal populations, the molecular signatures of which are largely unknown. To identify and characterize selectively vulnerable neuronal populations, we used single-nucleus RNA sequencing to profile the caudal entorhinal cortex and the superior frontal gyrus – brain regions where neurofibrillary inclusions and neuronal loss occur early and late in AD, respectively – from postmortem brains spanning the progression of AD-type tau neurofibrillary pathology. We identified RORB as a marker of selectively vulnerable excitatory neurons in the entorhinal cortex, and subsequently validated their depletion and selective susceptibility to neurofibrillary inclusions during disease progression using quantitative neuropathological methods. We also discovered an astrocyte subpopulation, likely representing reactive astrocytes, characterized by decreased expression of genes involved in homeostatic functions. Our characterization of selectively vulnerable neurons in AD paves the way for future mechanistic studies of selective vulnerability and potential therapeutic strategies for enhancing neuronal resilience.

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Faculty Opinions recommendation of Investigation of the human brain metabolome to identify potential markers for early diagnosis and therapeutic targets of Alzheimer's disease.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.718010574.793476741 ◽

2013 ◽

Author(s):

Laetitia Davidovic

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Early Diagnosis ◽

Human Brain ◽

Therapeutic Targets

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The Therapeutic Potential of Purinergic Receptors in Alzheimer’s Disease and Promising Therapeutic Modulators

Mini-Reviews in Medicinal Chemistry ◽

10.2174/1389557520999201209211610 ◽

2020 ◽

Vol 20 ◽

Author(s):

Lili Pan ◽

Yu Ma ◽

Yunchun Li ◽

Haoxing Wu ◽

Rui Huang ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Purinergic Receptors ◽

Therapeutic Potential ◽

Purinergic Signaling ◽

Memory Loss ◽

Related Research ◽

Central Nervous System Disorders ◽

G Protein Coupled

Abstract:: Recent studies have proven that the purinergic signaling pathway plays a key role in neurotransmission and neuromodulation, and is involved in various neurodegenerative diseases and psychiatric disorders. With the characterization of the subtypes of receptors in purinergic signaling, i.e. the P1 (adenosine), P2X (ion channel) and P2Y (G protein-coupled), more attentions were paid to the pathophysiology and therapeutic potential of purinergic signaling in central nervous system disorders. Alzheimer’s disease (AD) is a progressive and deadly neurodegenerative disease that is characterized by memory loss, cognitive impairment and dementia. However, as drug development aimed to prevent or control AD follows a series of failures in recent years, more researchers focused on the neuroprotection-related mechanisms such as purinergic signaling in AD patients to find a potential cure. This article reviews the recent discoveries of purinergic signaling in AD, summaries the potential agents as modulators for the receptors of purinergic signaling in AD related research and treatments. Thus, our paper provided an insight for purinergic signaling in the development of anti-AD therapies.

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Phenylalanine Metabolism is Dysregulated in Human Hippocampus with Alzheimer’s Disease Related Pathological Changes

Journal of Alzheimer s Disease ◽

10.3233/jad-210461 ◽

2021 ◽

pp. 1-14

Author(s):

Pan Liu ◽

Qian Yang ◽

Ning Yu ◽

Yan Cao ◽

Xue Wang ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Human Brain ◽

Pathological Examination ◽

Pathological Changes ◽

Targeted Metabolomics ◽

Phenylpyruvic Acid ◽

Postmortem Human Brain ◽

Metabolic Dysregulation ◽

Phenylalanine Metabolism

Background: Alzheimer’s disease (AD) is one of the most challenging diseases causing an increasing burden worldwide. Although the neuropathologic diagnosis of AD has been established for many years, the metabolic changes in neuropathologic diagnosed AD samples have not been fully investigated. Objective: To elucidate the potential metabolism dysregulation in the postmortem human brain samples assessed by AD related pathological examination. Methods: We performed untargeted and targeted metabolomics in 44 postmortem human brain tissues. The metabolic differences in the hippocampus between AD group and control (NC) group were compared. Results: The results show that a pervasive metabolic dysregulation including phenylalanine metabolism, valine, leucine, and isoleucine biosynthesis, biotin metabolism, and purine metabolism are associated with AD pathology. Targeted metabolomics reveal that phenylalanine, phenylpyruvic acid, and N-acetyl-L-phenylalanine are upregulated in AD samples. In addition, the enzyme IL-4I1 catalyzing transformation from phenylalanine to phenylpyruvic acid is also upregulated in AD samples. Conclusion: There is a pervasive metabolic dysregulation in hippocampus with AD-related pathological changes. Our study suggests that the dysregulation of phenylalanine metabolism in hippocampus may be an important pathogenesis for AD pathology formation.

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