N deg - 1 Characteristics of neurons u Cytoskeletal organization u Microtubules and motors u Neuronal intermediate filaments u Neurofilaments u Peripherin, Nestin u Microfilaments u Actins u Axonal transport u Fast transport u Slow transport

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3

4 Neurofilaments (EM)

N deg - 5 Neurofilaments (EM)

N deg - 6 Neurofilaments (biochemistry)

N deg - 7 Neurofilaments u Functions u Maintenance of the axonal organization u Radial growth u Mechanisms u Phosphorylation u Glycosylation?

N deg - 8 Axonal growth u Longitudinal growth u To establish the connection with targets u Growth cone u Early phase of Regeneration/Development u Actin and microtubules u Radial growth u To increase axonal caliber u Late phase of Regeneration/Development u Neurofilaments

N deg - 9 Neurofilaments and Axonal caliber u Inherent neuronal characteristics u Large targets with large axons u Developmental stage u Smaller caliber, less NF u Somatofugal axonal atrophy u Atrophy of the axons in the proximal stump after nerve injury u Related to NF synthesis, transport and phosphorylation

N deg - 10 Neurofilaments and Axonal caliber (Experimental evidence) u Correlation between caliber and NF number u Development u Degeneration/Regeneration u Genetics u Transgenic mice to delete NFs u Spontaneous mutant: Japanese quail

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N deg - 13 NF: Spontaneous mutant u Mutant Japanese quail u Lack of neurofilaments in axons; small axonal caliber u Growth normally, with some unsteadiness u Still susceptible to acrylamide: a model of neurofilamentous pathology u Mechanism: mutation in NF-L with a premature stop codon

N deg - 14 Transgenic mice with no NF u Absence of NFs due to deletion of NF-L gene u Small caliber with absence of NFs u Grow normally with neuronal swelling in spinal cords and axonal degeneration

N deg - 15 Transgenic mice with no NF

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N deg - 19 Neuronal swelling in NF transgenics u Over-expression of NFs u NF-H, NF-M, NF-L (ref) u Mutant or normal NFs u Pathology u Neuronal aggregates of NFs leading to neurodegeneration u Axonal atrophy and degeneration

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N deg - 21 Filamentous neuropathology u NF pathology u Neuronal u Early stage of ALS u Transgenics: NF, SOD u Axonal u Proximal: IDPN u Distal: 2,5-HD u Consequence: Neuronal death (Neurodegeneration)

N deg - 22 Filamentous pathology in neuronal cell bodies

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N deg - 25 Filamentous pathology in proximal axons

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N deg - 28 Wallerian degeneration u In the stump distal to the site of nerve injury u Degeneration of axons u Disintegration of axonal cytoskeleton and organization u Proliferation of Schwann cells u Infiltration of macrophages

N deg - 29 Neuronal response in Wallerian degeneration u Chromatolysis u Alteration in the patterns of mRNA u Somatofugal atrophy u Neuronal death in some situations

N deg - 30

N deg - 31 Neurodegenerative diseases u Cortex u Alzheimer disease u Frontotemporal dementia u Motor and coordination system u Motor neuron disease, Amyotrophic lateral sclerosis (ALS) u Parkinson’s disease u Spinocerebellar atrophy (SCA) u Autonomic system u Multiple system atrophy

N deg - 32 Filamentous neuropathology u MT pathology u Acrylamide u NF pathology u Neuronal u Early stage of ALS u Transgenics: NF, SOD u Axonal u Proximal: IDPN u Distal: 2,5-HD u Tau pathology u NFT in Alzheimer disease

N deg - 33 Alzheimer disease u Progressive dementia, particularly over age 65 u Basal foregbrain cholinergic hypothesis u Pathological hallmarks u Senile plaque u Neurofibrillary tangle

N deg - 34 Regenerative strategy for neurodegenerative diseases u Supplement of deficiency: cholinergic medications u Replacement of cells: stem cells, adrenergic cells u Establishment of connections: repulsive and attractive molecules

N deg - 35 神經再生 神經突起的再生 生長錐 (growth cones) 相吸物質 (attractants) 相斥物質 (repulsants)

N deg - 36 神經再生