Basic Science and Pathogenesis

Area of Science:

• Neuroscience
• Neuropathology
• Human tissue research

Background:

• Alzheimer's disease (AD) mechanisms are poorly understood due to limited early-stage human brain tissue.
• Idiopathic normal pressure hydrocephalus (iNPH) offers a unique model, as some patients exhibit early AD pathology.
• Surgically excised iNPH brain biopsies provide a novel human-based preclinical resource for AD research.

Purpose of the Study:

• To investigate the impact of early Alzheimer's disease (AD) related pathology on human neuronal function.
• To establish and utilize idiopathic normal pressure hydrocephalus (iNPH) brain biopsies as a preclinical model for AD.
• To correlate cellular and network-level electrophysiological changes with AD-related pathological markers.

Main Methods:

• Developed a pipeline to analyze neuronal properties in iNPH biopsies using patch clamp and multi-electrode array (MEA).
• Performed integrative analysis of human neuronal electrophysiology and cellular morphology.
• Correlated electrophysiological findings with existing AD-related pathologies (Aβ and tau).

Main Results:

• Amyloid-beta (Aβ) deposits decreased L1-induced inhibition and caused hyperexcitability.
• Increased global spine density was observed in pyramidal neurons with AD pathology.
• Neurons with both Aβ and tau showed intrinsic property deficits and increased bursting under NMDA stimulation.

Conclusions:

• This study is the first to demonstrate that Aβ and tau accumulation alter synaptic transmission and cortical network hyperexcitability in humans.
• iNPH biopsies serve as a valuable model for understanding how AD pathology affects neuronal network function.
• Findings highlight the potential of iNPH tissue for unraveling early AD pathogenesis.