CNS Degeneration

CNS Degeneration: Basic Mechanisms

Alzheimer’s Disease

Pathogenesis: loss of neurons accociated with memory (hippocampus, cortex)

Risk factors:

age (>54 age – 50% – free radical Ý , antioxidant defenses ß Þ oxidative stress)

family history

Down’s syndrome – develop identical neuropathological profile

Apolipoprotein E (Ý cholesteral, Ý LDL – ApoE > 6.5 mmol have Ý risk of alzheimers (1 to 3.1))

Vascular risk factors (hypertension)

low education

female (estrogen therapy – protects against alzheimers therefore Postmenoposal women at increased Ý risk)

head trauma

thyroid disease

psychological stress

depression

Pathological lesion: neurofibrillary tangles and senile plaques

Selective neuronal loss: pyramidal neurons of the cerebral cortex and hippocampus

neurotransmitter alterations and/or excitotoxicity: aluminum glutamate, cholinergic toxin

Mechanism of neurodegeneraion: two theories based upon cytoskeletal abnormalities

essential question: which comes first, the plaques (via amyloid-ß) or the tangles (via t proteins)?

(1) t (tau) protein – might form neurofibrilary tangles that later lead to senile plaques

Progression: t protein Þ neurofibrillary tangle Þ senile plaque (amyloid b protein contributing to plaque)

t protein function: binds to and stabilizes protein polymers (tubulin, actin, neurofilament) Þ becomes phosphorylated Þ microtubules disassemble (no axonal tranport) Þ degeneration

Phosphorylation hypothesis – tangle can form with Ý kinase activity, ß phosphatase activity

Problem: mitosis paradox Þ activity is identical to mitotic activity which do not develop neurofibrillary tangles.

Therefore t is an important marker, but what it does is unknown

(2) b amyloid protein – senile plaque formation

b amyloid protein Þ senile plaque Þ neurofibrillary tangle (Tau contributing to tangle)

Amyloid b (normal soluble cellular protein (ab ) – derived from larger amyloid precursor protein (in cytoskeleton) by secretases

Hypothesis: Soluble (amyloid b ) fibers Þ insoluble fibers

Evidence: mutation in precursor protein develops Alzheimers (100%)

Predisposing Genetic factors: certain mutations Ý amyloid secretion from certain cells (Chr 21, 19, 14, 1)

Problems with hypothesis: cerebellum possesses b -amyloid but no neuronal death associated with Alzheimers in these areas. Therefore amyloid is necessary but does not cause neuronal death.

Oxidative damage

Oxidative stress is the first event seen pathologically, probably plays a role in the cytoskeletal abnormalities seen in ALL neurodegenerative diseases

Source of oxidative stress – Free radicals (unpaired electrons) from mitochondria in respiratory chain Þ will pair up with anything Þ damage – DNA (mito/nucear), lipids, protein (crosslinked and insoluble)

Why are neurons susceptible? -Ý levels of unsaturated membrane fatty acids (lipid peroxidation), Ý O₂ demand (brain uses 20%), Ý levels of ascorbate and Fe (substantia nigra), ß antioxidant capacity

Neurofilaments may be more susceptible to oxidative damage:

Neurofilaments are transported down the axon by the slowest component of axonal transport and therefore have a long half life. Neurofilament protein half-life is dependent on axonal length, which may help explain the selective vulnerability of motor neurons in ALS.

The molecular structure of neurofilaments is rather unusual in that the two largest subunits, medium and heavy, contain tails with multiple lysine residues making neurofilaments an ideal substrate for oxidative attack.

Possible Treatment: antioxidant therapy (ß progression/incidence), Diet (Ý antioxidant consumption – fruits + vegetables, calorie restriction – shown to ß incidence of Alzheimer) Cholinesterase – symptomatic relief by blocking ApoE, Block secretases thereby preventing amyloid formation and senile plaque formation

Parkinson’s Disease

Pathological lesion: Lewy bodies

Selective neuronal loss: the pigmented neurons of the brainstem

Neurotransmitter alterations and/or excitotoxicity in: MPTP (toxin capable of killing dopamine neurons of substantia nigra), glutamate

Amyotrophic Lateral Sclerosis

Pathological lesion: spheroids

Selective neuronal loss: the motor neurons of the spinal cord and cerebral cortex.

Superoxide dismutase (SOD): Genetic findings showing linkage to mutations of the superoxide dismutase (SOD) gene in some cases of familial ALS. Mice that are made transgenic for mutated SOD develop many of the pathological and phenotypic characteristics of ALS. But the mechanism is unknown: free radicle?