1. 1 Bi / CNS 150 Lecture 23 Friday November 22, 2014 Neurodegenerative diseases Bruce Cohen Kandel, Chapters 43, 44 (p. 1002 - 1012), 59

2. Neurodegenerative Diseases Neurodegenerative diseases are characterized by an abnormal loss of neurons that begins in middle age or later and progressively increases until death They are not considered part of normal aging Neurodegenerative diseases typically result in the formation of atypical, sub- cellular protein assemblies such as amyloid plaques, neurofibrillary tangles, or lewy bodies The three most common neurodegenerative diseases are Alzheimer disease (AD), Parkinson’s disease (PD), and Amyotrophic lateral sclerosis (ALS) 2

3. Alzheimer’s Disease Initially described by Alois Alzheimer in 1901 Disease progression I.Starts with memory loss and impaired cognitive abilities II.Middle stage, I.individuals may forget how to do simple tasks, like brushing their teeth or combing their hair II.They can no longer think clearly III.have problems speaking, understanding, reading, or writing. III.Late stage, patients become anxious or aggressive, or wander away from home. IV.Eventually, patients need total care. 3

4. Age is major risk factor for Alzheimer’s disease (AD) AD is the most common degenerative brain disease (est. 5 million USA, 25 million globally) The major risk factor is age AD is not considered normal aging (even though 50% of people older than 85 show signs) Most common form of AD (late-onset or sporadic AD) occurs late in life without obvious inheritance pattern. Several risk factor genes may interact to cause the disease. Most common genetic risk factor for late-onset AD is inheritance of a particular type of apolipoprotein E (apoE) called ApoE4 (prevalence ~ 16%), two copies of which produce a 3-4 fold dominant increase. Familial AD, which is rarer, starts at age 30 - 60. 65-747580>85 ~5%~10%~20%~50% 4

5. Cytological Hallmarks of Alzheimer’s Pathology: Amyloid Plaques and Neurofibrillary Tangles in Brain Amyloid plaques contain large amounts of 42 amino acid peptide termed “  - amyloid”, or A  42  -amyloid itself causes initial pathophysiology that leads to dementia Amyloid plaques probably contribute to the later stages of pathology Neurofibrillary tangles are rich in cytoskeletal proteins, especially the microtubule-associated protein, “tau”. In tangles, there are heavily phosphorylated proteins which may cause aggregation and precipitation of the cytoskeleton. Also, AD reduces brain volume, especially in entorhinal cortex and hippocampus 5

6. Presenilin 1 and APP mutations are associated with familial AD Hardy and Selkoe, 2002, Science presenilin 1 is part of  -secretase, a membrane-associated protease 6

7. AD pathophysiology caused by proteolytic products from APP called Aβ40 and Aβ42 Overproduction of A  40 and A  42 results from altered ratio of proteolytic cleavages at sites termed , , and . β-APP is amyloid precursor protein. APP proteins are 10 to 140 kDal. APP expressed by most tissues, especially neurons Found in axon terminals, dendrites, and glial cells. Kandel et al.,Principles of Neural Science © McGraw-Hill Professional Publishing 7

8. Genetic risk factors for AD increase accumulation of Aβ peptides ChromosomeGene defectPhenotype 21β-APP mutations A673T is an APP mutation that is neuroprotective for AD ↑All Aβ peptides, or Aβ40 peptides ↓ Aβ peptides, AD, cognitive decline 19ApoE4 polymorphism (ε4 allele) ↑Density of Aβ plaques & vascular deposits 14Presenilin 1 mutation↑Production of Aβ42 peptides 1Presenilin 2 mutation↑Production of Aβ42 peptides 6TREM2↑Density of Aβ plaques “Aβ (especially Aβ42) microaggregates—also termed “soluble Aβ oligomers” or “Aβ-derived diffusible ligands” (ADDLs)—constitute the neurotoxic species that causes AD” – Sheng, 2012 Abnormal states of tau mediate some effects of β-amyloid. This stage may be distal to the more toxic dimers and oligomers. 8

9. (Injected into ventricles 10 min before high frequency stimulation of the rat Schaffer collateral pathway). Walsh et al., Nature 2002 CM = “conditioned medium” from a cell line engineered to express Aβ Wild Type CM CM + Aβ oligomers CM + nonspecific “control” antibody CM + Antibody against Aβ Soluble Aβ oligomers block induction of long-term potentiation 9

10. James Parkinson, apothecary surgeon described "paralysis agitans” from observations of 6 individuals during his daily walks in London in An Essay on the Shaking Palsy (1817)An Essay on the Shaking Palsy Classic motor symptoms: tremor at rest 3-5 Hz, “pill-rolling” slow movements, particularly when initiating locomotion short, rapid steps http://www.youtube.com/watch?feature=endscreen&v=j86omOwx0Hk&NR=1x Dramatization of the motor problems in a PD patient Parkinson’s disease 10

11. Rodent brain section, stained for tyrosine hydroxylase: coronal view Selective loss of dopaminergic neurons in the human brain causes motor signs of PD Substantia Nigra: Dopaminergic neurons die in PD 11

12. Flow chart of motor system hierarchy 12

13. 13 The Basal Ganglia: Major inputs “striatum” 13

14. 14 Basal ganglia-thalamocortical circuit Basic wiring of basal ganglia Cortical neurons excite medium spiny neurons (MSNs) in Putamen (upper right) MSNs receive modulatory input from dopaminergic neurons in Substania Nigra pars compacta (SNc) MSNs are GABAergic and inhibit neurons in the Globus Pallidus internal (Gpi) and external segments (GPe) Dopaminergic input to MSNs leads to inhibition of GPi neurons and disinhibits thalamic and pedunculopontine neurons Disinhibition of these neurons allows voluntary motor movements Loss of dopaminergic neurons in SNc impairs initiation of voluntary movement

15. Intracellular “Lewy bodies” in dopaminergic neurons are hallmark of PD pathology Lewy bodies can also occur in other diseases such as frontotemporal dementia 15

16. 16  -synuclein has an unknown function; it’s an “intrinsically disordered protein”. Mutant  -synuclein forms fibrils. Improper mitochondrial fission / fusion may be an early event The hallmark of PD pathology: Intracellular “Lewy bodies”, especially in dopamine neurons

17. levodopa, “L-dopa” zwitterion permeates into brain via a transporter dopamine does not enter brain enzyme: decarboxylase Used with carbidopa, which inhibits decarboxylase. Prevents hydrolysis in the blood and in the peripheral nervous system. D2 receptor agonist is often added. This seems to reduce dyskinesias PD treated with L-dopa 17

18. Deep brain stimulation for Parkinson’s disease Stimulting electrode placed in subthalamic nucleus (STn) Tuned to frequencies that inactivate STn activity Nestler, Hyman, Malenka, Molecular Neuropharmacology, © McGraw-Hill Professional Publishing 18 https://www.youtube.com/watch?v=a_4_DvquSYQwww.youtube.com/watch?v=a_4_DvquSYQ

19. 19 1.Alzheimer’s disease (AD) produces overall loss of neurons 2.AD causes formation of amyloid plaques 3.Accumulation of soluble Aβ oligomers appears to cause neuronal damage in AD 4.Parkinson’s disease (PD) creates problems with voluntary motor movements 5.Motor symptoms in PD due to loss of dopaminergic neurons in SNc 6.PD causes formation of Lewy bodies in neurons Bruce Cohen’s office hours, 1:15-2 328 Kerckhoff