1

Bi / CNS 150

Lecture 23

Friday November 22, 2014

Neurodegenerative diseases

Bruce Cohen

Kandel, Chapters 43, 44 (p. 1002 - 1012), 59

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

Alzheimer’s Disease

Initially described by Alois Alzheimer in 1901

Disease progressionI. 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 clearlyIII. 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

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.

65-74 75 80 >85

~5% ~10% ~20% ~50%

4

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 A42

•-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

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

AD pathophysiology caused by proteolytic products from APP called Aβ40 and Aβ42

Overproduction of A40 and A42 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

Genetic risk factors for AD increase accumulation of Aβ peptides

Chromosome Gene defect Phenotype

21 β-APP mutations

A673T is an APP mutation that is neuroprotective for AD

↑All Aβ peptides, or Aβ40 peptides

↓ Aβ peptides, AD, cognitive decline

19 ApoE4 polymorphism(ε4 allele)

↑Density of Aβ plaques & vascular deposits

14 Presenilin 1 mutation ↑Production of Aβ42 peptides

1 Presenilin 2 mutation ↑Production of Aβ42 peptides

6 TREM2 ↑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

(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

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)

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

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

Flow chart of motor system hierarchy

12 12

13

The Basal Ganglia: Major inputs

“striatum”

13

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

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

-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

levodopa, “L-dopa”zwitterion

permeates into brainvia a transporter

dopamine

does not enter brain

enzyme:decarboxylase

HO

HO

H2C NH3

+

CO2-

HO

HO

H2C

CH2

NH3+

Used with carbidopa, which inhibits decarboxylase.

Prevents hydrolysis in the blood and in the peripheral nervous system. HO

HOH2C

C

HN

NH3+

CO2-H3C

D2 receptor agonist is often added. This seems to reduce dyskinesias

PD treated with L-dopa

17

•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

18https://www.youtube.com/watch?v=a_4_DvquSYQ

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