Biology of Alzheimer’s Disease
Summary: The Amyloid plaques, pathways, and proteins.
Using a microscope to evaluate the AZ brain.
Amyloid Plaques
Although various forms of dementia including Alzheimer’s Disease (AZ), vascular dementia, and Lewy Bodies involve neurodegeneration, what sets AZ apart from the others is its biological processes. Pathologists found amyloid plaques (amyloid alpha-beta protein) inside the brain of AZ patients, and subsequently noticed fibrillary tangles around the nerves.
Alois Alzheimer found plaques and neurofibrillary tangles in the brain of a 51 year old woman who died with dementia (1906), while Paul Blocq and Georges Marinesco (1892) described senile plaques.
References: history-biography.com and n.neurology.org
DNA mutations are seen in AZ.
Amyloid Pathways
The normal forerunner protein is called Amyloid Precursor Protein (APP), a transmembrane protein in neuronal cells, which is broken down by beta secretase and gamma-secretase enzymes. Using protein and DNA technologies, scientists later found potential culprits that likely participate in the genesis of AZ. For example, the mutations of Apolipoprotein E (APOE) allele Epsilon4, Amyloid Precursor Protein (APP) gene, Presenilin genes may result in the buildup of abnormal protein plaques and/or Tau tangles or fibrils. Scientists now describe the series of steps as Amyloid cascade and Hyperphosphorylated Tau pathways.
Complex interactions of abnormal proteins are found in AZ.
Abnormal Proteins
Although the pathological degradation of Beta Amyloid protein results in abnormal “toxic” fragments that are misfolded (alpha beta oligomeric peptides) that can activate inflammation, oxidative stress, calcium dysregulation, and TAU phosphorylation by kinases, the precise mechanisms are not clear. The normal forms of the proteins and peptides likely protect the brain. Clearance of alpha beta peptides by APOE and insulin degrading enzyme (IDE), likewise involve complex regulation that require future understanding.
Therefore the biology of AZ likely needs either the generation of abnormal proteins and/or the inefficient clearance of subsequent toxic peptides. There are many drugs directed against specific protein/enzyme targets based on these complex pathways, but the potential benefits in treatment may require a combination of drugs and lifestyle changes.
REFERENCES:
