Neurodegenerative lesions: seeding and spreading

Area of Science:

• Neurobiology
• Neuropathology
• Molecular Biology

Background:

• Neurodegenerative diseases are increasingly defined by abnormal protein accumulation rather than solely neuronal loss.
• While mutations can alter protein structure, most disease-associated proteins have a normal primary sequence.
• Pathological hallmarks in Alzheimer's, Parkinson's, and progressive supranuclear palsy suggest disease spread follows neuroanatomical pathways.

Purpose of the Study:

• To investigate the prion-like mechanisms of protein misfolding and aggregation in neurodegenerative diseases.
• To explore whether exogenously introduced protein aggregates can initiate disease pathology in experimental models.
• To understand the cellular mechanisms, such as endocytosis and transport, involved in the propagation of misfolded proteins.

Main Methods:

• In vivo studies involving the injection of protein aggregates (Aβ, tau, alpha-synuclein) into the brains of transgenic and wild-type mice.
• In vitro cell culture experiments to assess protein uptake and transport by neurons.
• Analysis of neuropathological hallmarks in experimental models to mimic human disease progression.

Main Results:

• Brain homogenates with amyloid-beta (Aβ) aggregates induced Aβ deposition in APP transgenic mice.
• Tau aggregates from human tauopathies induced tau pathology in mice expressing normal human tau.
• Synthetic alpha-synuclein fibrils initiated Parkinson's-like pathology in wild-type mice.
• Cell culture data indicated that specific oligomeric or fibrillar states are necessary for protein endocytosis and neuronal transport.

Conclusions:

• The protein accumulating in neurodegenerative diseases is initially misfolded.
• This misfolded protein can contaminate normal proteins in a prion-like manner, driving disease progression.
• Neuronal connections play a critical role in the cell-to-cell transmission of these misfolded proteins.