Pathology of Neurodegenerative Disease Flashcards
2 Key Hallmarks in AD Brain
- Amyloid plaques (extracellular; accumulate between neurons in the brain)
- Neurofibrillary Tangles (intracellular; NFT; aggregate of hyperphosphorylated Tau protein)
Amyloid Precursor Protein (APP)
Integral membrane protein (membrane spanning)
Cut at B secretase: Get C99
Cut at A secretase: Growth factor is released
Cut at G secreatse: AICD (modulator for cytoskeleton, gene expression, apoptosis)
Cut at B and G secreatse: Beta amyloid & AICD
C99
When cut is made at B secretase
Integral membrane protein with regions of intrinsic disorder
Has A-helical protein that spans the bilayer of micelle
Has intrinsically disordered protein that is very flexible
Normal APP
Normal cleavage of APP
Form normal amounts of AB peptide (unknown normal function) >
Form toxic AB oligomers >
Cell fixes toxicity through degradation
Alzheimer APP
Something is wrong with degradation of toxic oligomers
Fibers build up outside cell
Oligomers build up and for Amyloid Beta sheet fibers, which are exported outside the cell
Not sure what causes the neurodegeneration
Possible Molecular Mechanisms of AB Toxicity in AD
Toxic AB oligomers adhere to membranes and proteins and can form unregulated pores in membranes
AB starts dispersed throughout cell, aggregates, forms short fibers, forms long fibers
Normal Tau Neurofibrillary Tangles
Normal tau: 50-75 kDa (>400 aa - very large); 6 splice variant isoforms (huge range of size; intrinsically disordered
Physiologic amount of hyperphosphorylated tau
Promotes microtubule assembly
Maintains microtubule structure
Alzheimer Tau NFT
4-8x physiologic hyperphosphorylated tau
Abnormal tau that does not bind/stabilize microtubules, forms Tau tangles
Molecular Mechanisms of APP and Tau
Unknown initiating event
1. Altered APP post translational modification (common in familial cases where AB is produced)
»>Leading to altered AB folding
OR 1. Altered Tau post translational modification
»>Leading to Tau aggregation
Do these things cause the pathological cellular change/neurodegeneration? Or does the unknown initiating even cause it? Could APP be causing Tau?
Amyloid Plaque PET Scan
Patient is injected with ligand that binds to AB plaque
No plaque: ligand washes through
Plaque: Ligand sticks to plaque and releases signal that is seen by PET
Negative: Normal for ligand to stick to the white matter and turn it gray, but this is not what we are looking at. Looking more towards the exterior, which remains lighter colored, showing no plaque aggregation; As you get closer to cortex, signal goes away
Positive: Shows darker color due to ligand sticking to plaque; As you move medially, signal becomes more pronounced
Fluorodeoxyglucose PET Scan
Tracer is in the form of glucose that cannot be fully metabolized
Distribute throughout brain according to demand for glucose
Areas with higher demand for glucose utilization will send more, red fiery signal
In AD: Posterior temporal and parietal cortex use less glucose than normal, resulting in loss of signal/less red.
Especially in posterior cingulate region: Should be very bright in normal function
Magnetic Resonance Spectroscopy
Often in research, not yet in clinical
Instead of organizing data from MRI to make structural images, data is used to give info on levels of certain metabolites & chemicals
Ex. NAA: Neurochemical found in mito. and neurons. In AD, NAA levels decrease due to a loss of neurons or mito. mass.
Tangle PET Scan
New; recently entered research domain
Shows neurofibrillary tangles in brain, which accumulate in people with AD
Ligands designed to stick to NFT
Red: indicates presence of NFT
