Huntington’s Disease: Autosomal dominant disorder characterized by progressive neurodegeneration, usually most pronounced in the basal ganglia and cortex. Early symptoms include rapid flickering involuntary movements, including tics and grimaces. Later symptoms include dystonia, rigidity, and cognitive decline.

Parkinson’s Disease: Characterized by muscle rigidity, tremor, a slowing of physical movement (bradykinesia) and, in extreme cases, a loss of physical movement (akinesia). The primary symptoms are the results of decreased stimulation of the motor cortex by the basal ganglia, normally caused by the insufficient formation and action of dopamine normally produced in the substantia nigra.

Amyotrophic lateral sclerosis (ALS), sometimes called Lou Gehrig's disease, is a rapidly progressive, invariably fatal neurological disease in which the primary motor neurons in both upper and lower spinal cord degenerate or die, causing progressive weakness with a wide range of disabilities.

Movement Related Neurodegenerative Diseases

Neurodegenerative Diseases: Alzheimer’s Disease

Alzheimer’s Disease is a genetic disorder that can be inherited or

sporadic

A. Symptoms

B. Prevalence

C. Nature of gene mutations that predispose to Alzheimer’s

disease.

D. Major theories about the role of -amyloid in Alzheimer’s

disease.

Patient Presentation

Alzheimer’s Disease

I. Symptoms of Alzheimer’s diseaseA. AD begins slowly. At first, the only symptom may be mild

forgetfulness.B. In this stage, people may have trouble remembering recent

events, activities, or the names of familiar people or things. They may not be able to solve simple math problems. They may begin to repeat themselves every few minutes in conversation.

C. In the middle stages of AD, individuals may forget how to do simple tasks, like brushing their teeth or combing their hair. They can no longer think clearly. They begin to have problems speaking, understanding, reading, or writing.

D. Later on, people with AD may become anxious or aggressive, or wander away from home. Eventually, patients need total care.

II. Clue to Etiology: Alzheimer’s disease begins with a remarkably “pure” impairment of cognitive function.

Incidence and Public Health Costs

I. Alzheimer’s is the most common of the degenerative brain diseases.

II. As many as 4.5 million Americans suffer from AD. III. Risk Factors:

A. The disease usually begins after age 60, and risk goes up with age. About 5% of men and women ages 65 to 74 have AD. The number of people with the disease doubles every 5 years beyond age 65, and nearly half of those age 85 and older may have the disease. However, AD is not considered a normal part of aging.

B. Familial AD, a rare form that usually occurs between the ages of 30 and 60, is inherited. The more common form of AD, known as late-onset or sporadic AD, occurs later in life, and no obvious inheritance pattern is seen. However, several risk factor genes may interact with each other to cause the disease. The only clear risk factor gene identified so far for late-onset AD, is a gene that makes one form of a protein called apolipoprotein E (apoE). ApoE4 is the risk factor gene.

IV. The public health cost of Alzheimer’s disease is estimated at $90 billion per year in medical care costs and lost productivity.

The Hallmark of Alzheimer’s Pathology is the presence of Amyloid Plaques and Neurofibrillary Tangles in Brain Sections

Amyloid Plaques

Neurofibrillary Tangles

I. Amyloid Plaques were shown (1984) to contain large amounts of a 42 amino acid peptide termed “-amyloid”, or A42 The present most-favored hypothesis is that -amyloid itself is the initial cause of the chain of events that leads to dementia. Amyloid plaques are believed to contribute to the later stages of pathology

II. Neurofibrillary Tangles contain large amounts of cytoskeletal proteins, in particular the microtubule-associated protein named “tau”. Many of the tangle-associated proteins contain an unusually large amount of phosphate. The present favored hypothesis is that the excessive phosphorylation causes aggregation and precipitation of the cytoskeleton leading to formation of “tangles” that are visible in brain sections.

I. The family of APP proteins range in size from about 110 to 140 kDal. They have a large extracellular domain, a single transmembrane domain, and a small intracellular domain. Linkage analysis placed the gene on Chromosome 21.

II. APP is found in most tissues, but is most highly expressed in neurons, where it is transported to axon terminals, and dendrites. APP is also found in glial cells.

III. The normal functions of APP and related proteins are not yet known. Recent experiments suggest that it might play a role in trafficking of membrane vesicles to appropriate sites.

Beta-amyloid is formed by proteolytic cleavage of a protein termed Alzheimer’s Precursor Protein, or APP.

A40and A42 have been shown to be proteolytic products formed from APP

Overproduction of A40 and A42 results from subtle alteration in the ratio of proteolytic cleavages at sites termed ,, and.

Fig. 58-6, PNS

From Selkoe, Physiol. Rev., 2001

APP and its human mutations that lead to increased production of A peptides

I. A42 peptides form soluble oligomers of ~4 to 40 peptides. Eventually the oligomers interact with other proteins and precipitate to form Amyloid plaques.

II. An important advance in our understanding of the earliest pathology of Alzheimer’s disease was the finding in 1998 by Krafft and Klein at Northwestern that soluble oligomers of A42 (containing ~12 to 40 peptides) are toxic to neurons.

III. The toxic soluble oligomers are often called ADDLs (Alzheimer’s Disease Diffusible Ligands).

Soluble Oligomers of A42 (called ADDLs)

ADDLs block induction of LTP when injected into ventricles 10 min before high frequency stimulation of the Schaffer collateral pathway (in rat).

Wild Type CM

CM containing A oligomers

Antibody against A

Control Antibody

From Walsh et al., Nature 2002First discovery of importance of ADDL’s in 1998 from G. Krafft and W. Klein at Northwestern.

CM = “conditioned medium” from 7PA2

7PA2 = cell line producing A

Altered cleavage of APP by and proteases (called “ and secretases”) can lead to Alzheimer’s disease with early onset.

Fig. 58-6, PNS

Mutations in a protein termed Presenilin 1 are responsible for about 30% of early onset Familial Alzheimer’s disease

Red circles indicate mutations in APP and presenilin 1 that are found associated with Familial Alzheimer’s Disease.

From Hardy and Selkoe, 2002, Science 297, 353-356.

Presenilin is believed to be a critical subunit of the -secretase

From Hardy and Selkoe, 2002, Science 297, 353-356.

(Tace)

-secretase is an active aspartate membrane-associated protease.

Presenilin’s -secretase normally participates in Notch signaling

From Selkoe, 2002, Science 298, 789.

Mutations in either APP or a protein termed “presenilin” can cause familial Alzheimer’s disease.

Sporadic Alzheimer’s appears to result from gradual failure of clearance of A. Inheritance of ApoE4 is a risk factor for sporadic Alzheimer’s disease.

QuickTime™ and aTIFF (Uncompressed) decompressor

are needed to see this picture.

1. Soluble oligomers of A- bind to synaptic sites

a) ADDL’s (12-mer and below)

b) A*56 (12 mer)2. Binding leads to internalization of AMPA and NMDA receptors.

3. Malinow et al. found that activity increases amount of APP and A-. They postulate that these events may be part of a normal homeostatic mechanism that becomes deranged in Alzheimer’s disease.

Current Hypotheses

From J. Neurosci. (2007) 27: 11832

All known genetic risk factors predisposing to Alzheimer’s disease increase accumulation of A

peptides

From Selkoe, Physiol. Rev., 2001

I. Much current research now focuses on the early effect of soluble oligomers of A42 on synaptic function in the hippocampus and cortex.

A. Evidence from animal studies indicates that soluble oligomers may lead to a reduction in basal levels of synaptic transmission in the hippocampus

B. Under some circumstances, they have also been shown to dramatically inhibit long-term potentiation.

C. These pathological changes may eventually lead to the dramatic neuronal loss associated with late stage Alzheimer’s

II. New therapeutic strategies will likely focus on this aspect of the disease

Early Alzheimer’s disease is associated with synaptic failure