From the Guidelines
Neurofibrillary tangles in cortical neurons are primarily caused by the abnormal hyperphosphorylation and misfolding of tau proteins, as supported by the most recent study 1.
Key Factors Contributing to Neurofibrillary Tangle Formation
- Dysregulation of kinases and phosphatases that control tau phosphorylation
- Oxidative stress
- Inflammation
- Genetic factors
- Accumulation of beta-amyloid plaques, which may trigger tau pathology through various signaling pathways
Process of Neurofibrillary Tangle Formation
Tau is normally a stabilizing protein that helps maintain the structure of microtubules in neurons. However, when it becomes hyperphosphorylated, it detaches from microtubules and aggregates into paired helical filaments. These filaments then form the characteristic neurofibrillary tangles seen in neurodegenerative diseases like Alzheimer's disease.
Consequences of Neurofibrillary Tangle Formation
Once formed, these tangles disrupt axonal transport, compromise neuronal function, and eventually lead to neuronal death. The process typically begins in the entorhinal cortex and hippocampus before spreading to other brain regions, following a predictable pattern that correlates with cognitive decline in Alzheimer's disease and other tauopathies.
Diagnostic Considerations
The diagnosis of neurofibrillary tangles can be supported by biomarkers such as cerebrospinal fluid (CSF) analysis, which can detect abnormal levels of tau and beta-amyloid proteins 1. Imaging techniques like positron emission tomography (PET) can also be used to visualize amyloid plaques and tau deposits in the brain.
Recent Recommendations
Recent guidelines recommend the use of CSF analysis and imaging techniques like FDG PET to support the diagnosis of Alzheimer's disease and related disorders 1. These guidelines also emphasize the importance of considering the clinical context and using a combination of biomarkers to increase diagnostic accuracy.
Clinical Implications
Understanding the causes and consequences of neurofibrillary tangle formation is crucial for the development of effective therapeutic strategies for Alzheimer's disease and other tauopathies. Early diagnosis and intervention may help slow disease progression and improve patient outcomes.
From the Research
Causes of Neurofibrillary Tangles
- Neurofibrillary tangles (NFTs) in cortical neurons are primarily composed of hyperphosphorylated tau protein 2, 3, 4.
- The formation of NFTs is associated with various neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, and frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP17) 3.
- Transient cerebral ischemia can induce site-specific hyperphosphorylation of tau protein, leading to the formation of NFTs 3.
- Abnormally hyperphosphorylated tau protein can accumulate in cortical neurons, contributing to brain damage and potentially leading to neurodegenerative disorders 3, 5.
- The regional distribution of tau proteins differs among various neurodegenerative disorders, including Alzheimer's disease and amyotrophic lateral sclerosis/parkinsonism-dementia complex of Guam 4.
Role of Tau Protein
- Tau protein is a microtubule-associated protein that plays a crucial role in maintaining microtubule stability 6.
- Hyperphosphorylation of tau protein leads to its aggregation and the formation of NFTs 2, 3, 4, 6.
- An imbalance of kinase and phosphatase activities can lead to the abnormal phosphorylation of tau protein 6.
Therapeutic Targets
- Tau protein is a potential therapeutic target for Alzheimer's disease and related tauopathies 6.
- Various therapeutic approaches are being developed to target tau protein, including inhibiting tau kinases, enhancing phosphatase activity, promoting microtubule stability, and reducing tau aggregate formation and/or enhancing their clearance 6.