Table of Contents
Human Prion Diseases
Genetic Basis to AD
Hypothetical Sequence of familial AD
REVIEW- Impaired synaptic plasticity and learning in aged amyloid precursor protein transgenic mice
Methods - additional points
Normal Synaptic Physiology in area CA1 and Dentate Gyrus in slices
Impaired LTP in 16 month but not 2-8 month old transgenics in slices
Normal PPF suggesting normal short-term presynaptic plasticity in slices
Impaired LTP in transgenic dentate gyrus in vivo
Aged but not young APP transgenic mice show impaired spatial learning
Only a small percentage of the transgenics reach the 80% criterion at 16 months
Correlation between LTP in slices from area CA1 and T-maze performance during last 2 days
Correlation between LTP in slices from Dentate Gyrus and T-maze performance during last 2 days
Start here Wed. Sensorimotor and emotional behavioral within normal range so that effects appear to be on memory only
The APP transgenic mice show levels of A? (amyloid protein) comparable to those found in Human AD
Slices from the Electrophysiology Experiments revealed A? plaques (orange) in hippcocampus.
Summary
Synapses? Neurons?
Cholinergic Synapses in mice with Mutated Presenilin-1 & APP
Evaluate Cholinergic Synapses in this double mutation at 8 months.
At 8 months have A) AD-like plaques and B) Dystrophic cholinergic neurites
Normal variation across brain regions in density and size of VAChT-IR presynaptic boutons
LM of VAChT - immunoreactivity
Hippocampus - decrease in VAChT-IR bouton size
Frontal Cortex decrease in density and size
Other brain regions show no effect in cholinergic innervation in any of the transgenics at 8 months
Age-Dependent Neuronal and Synaptic Degeneration in Mice
Methods
Neuronal Degeneration and dark dendrites among dentate granule cells from a 23-month-old Flag-APP-C100 male mouse
Hippocampal area CA1Pyramidal cells from 28 month male also show substantial degeneration and dark neurites (dark cells)
Neuronal and neurite degeneration already present at 14.5 month old Flag-APP-C100 mice
Very little neuronal degeneration in control 22 and 24 month old mice
Normal Hippocampal Neuropil has Well-spaced Interneurons with very few duets with nearby glia (red).
Both healthy and degenerating neurons in 24 month APP-C100 mouse show aberrant 2ndary lysosomes (white), and nearby microglial cells (red circles)
Another Example -2ndary lysosomes (arrows) and microglia (red circles) in 24 month APP-C100 mouse
28 Month Male APP-C100
2ndary lysosomes less common in aged controls (though no numbers given!)
Lysosomes and lipid vacuoles common in the APP-C100 founder mice even at the relatively young age of 14.5 months
Degenerating synaptic neuropil in 28 month C100-APP mice
Behavioral effects in C100-APP mice
Normal Locomotion
Impaired performance on Morris Water Maze Probe test
Fewer Healthy Hippocampal Neurons in the C100-APP mice
Conclusion
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