Basic Science and Pathogenesis

Area of Science:

• Neuroscience
• Molecular Biology
• Genetics

Background:

• Entorhinal cortex layer II (ECII) neurons are primary sites for tau pathology in preclinical Alzheimer's disease (AD).
• The early pathological cascade and transcriptional changes in EC neurons leading to neurofibrillary tangles are poorly understood.
• Understanding these early changes is crucial for identifying therapeutic targets before symptom onset.

Purpose of the Study:

• To profile cell-type-specific molecular alterations in the human entorhinal cortex (EC) at the earliest stages of AD neuropathology.
• To investigate molecular changes coinciding with incipient tau pathology in asymptomatic individuals.
• To identify potential multicellular mechanisms involved in early AD pathogenesis within the EC.

Main Methods:

• Single-nucleus RNA sequencing (snRNA-seq) of postmortem human EC tissue from asymptomatic individuals.
• Fluorescence-activated neuron nucleus sorting (FANS) for cell-type specific analysis.
• Immunofluorescence and multiplex in situ hybridization to validate findings and identify specific pathways and neuron types.

Main Results:

• Early glial response, particularly by disease-associated microglia, to amyloid pathology was observed.
• Dysregulation of the Reelin signaling pathway in ECII neurons was identified, coinciding with incipient tau pathology.
• Downregulation of synaptic organizer molecules NPTX2 and CBLN4, potential AD biomarkers, in surrounding neurons suggests a multicellular mechanism.

Conclusions:

• The study reveals a complex multicellular landscape in the EC during the silent phase of AD.
• Identified pathway dysregulation and cell-cell communication provide insights into early neurodegeneration mechanisms.
• Findings open novel therapeutic avenues for targeting early AD pathogenesis and neurofibrillary tangle formation.