Table of Contents
Synapse Pathology especially with Alzheimer’s Disease
Dementias
Alzheimer’s Disease
Hallmarks of Alzheimer’s Disease
Normal Human Hippocampus
Presence of diffuse amyloid plaques throughout many brain regions
Diffuse amyloid plaques Human AD Cortex
Mature Plaques with prominent neuritic reaction, neurofibrillary tangles and neuropil threads in Human AD cortex
EM of mature plaque with characteristic fibrillar organization of amyloid protein
Neurofibrillary Tangles assume shape of Neurons in AD brains
EM of intracellular neurofibrillary tangle in AD brain
Neurofibrillary Tangles and Tau (axonal microtubule associated protein)
Spongy Vacuolation in cortex in some cases of AD
Dendritic Atrophy - AD Cortical Neurons
Loss and structural changes in AD dendritic spines
Occasional Odd Dendritic Hypertrophy on AD Neurons
Synapse loss compensated by enlargement in both Aged control, and AD brains
Genetic Basis to AD
Impaired synaptic plasticity and learning in aged amyloid precursor protein transgenic mice
Methods
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
Aged Transgenics never reach criterion of their age-matched littermate controls 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 the right locations.
Summary
Age-Dependent Neuronal and Synaptic Degeneration in Mice
Granule cell layer
Pyramidal cell layer of 28-month-old heterozygous male
Pyramidal cell layer of male 14.5-month-old
Pyramidal cell layer of 22-month-old male
Neuropil of hippocampal formation of 24-month-old
Neuropil of hippocampal formation of 24-month-old female
Neuropil of hippocampal formation of 24-month-old female
Aberrant secondary lysosomal inclusions of 28-month-old male
Secondary lysosomes in 22-month-old male
Secondary lysosomes in 14.5-month-old male line-one founder mouse
Degenerating synapses in neuropil of 28-month-old male
Neuropil of the underlying dentate gyrus of the hippocampal formation of the same 28-month-old male
Synapses Fig. 14.1
Synapses Fig. 14.2
Synapses Fig. 14.3
Synapses Fig. 14.4
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