Protein misfolding diseases- Alzheimer disease and Prion disease

1. Protein misfolding diseases
Alzheimer’s disease
Case Details
An 80 –year-old man presented with impairment of brain functions, alterations of mood, and
behavior. His family reported that he had progressive disorientation and memory loss over the
past six months. He had trouble handling money and paying bills. He repeated questions, took
longer to complete routine daily tasks, had poor judgment, and had developed mood and
personality changes.
There was no family history of dementia. The routine blood, urine, and C.S.F analysis did not
reveal much. After a computerized tomography (CT) scan and the histopathological
examination of the brain tissue, the patient was diagnosed having Alzheimer disease.
What is the defect in this disease?
How is the diagnosis made, and what is its prognosis?
Case discussion
Basic Concept
Alzheimer’s disease is defined as premature aging of the brain, usually beginning in mid-adult
life and progressing rapidly to extreme loss of mental powers—similar to those seen in very,
very old age.
Clinical features
Alzheimer’s disease is a progressive and fatal neurodegenerative disorder that results in
impairment of a person” ability to perform routine activities. The patient finally enters into a
vegetative state with no comprehension of the outside world. The disease runs in four stages:
i) Pre dementia, ii) Mild dementia, iii) Moderate dementia, and iv) Advanced dementia.
Although the course of Alzheimer's disease is unique for every individual, there are many
common symptoms. The earliest observable symptoms are often mistakenly thought to be
'age-related' concerns or manifestations of stress. In the early stages, the most commonly
recognized symptom is memory loss, such as difficulty in remembering recently learned facts.

2. As the disease advances, symptoms include confusion, irritability and aggression, mood swings,
language breakdown, long-term memory loss, and the general withdrawal of the sufferer as
their senses decline. Gradually, bodily functions are lost, ultimately leading to death.
Biochemical defect
Alzheimer's disease has been identified as a protein misfolding disease caused by the
accumulation of abnormally folded A-beta and tau proteins in the brain. Plaques are made up
of small peptides, 39–43 amino acids in length, called beta-amyloid (also written as A-beta or
Aβ). Beta-amyloid is a fragment from a larger protein called amyloid precursor protein (APP), a
transmembrane protein that penetrates through the neuron's membrane. APP is critical to
neuron growth, survival, and post-injury repair.
In Alzheimer's disease, an unknown process causes APP to be divided into smaller fragments by
enzymes through proteolysis. One of these fragments (Aβ peptide) gives rise to beta-amyloid
fibrils, which form clumps that deposit outside neurons in dense formations known as senile
plaques. (Figure-1)
AD is also considered a tauopathy due to abnormal aggregation of the tau protein. Every
neuron has a cytoskeleton; an internal support structure partly made up of structures called
microtubules. These microtubules act like tracks, guiding nutrients and molecules from the
body of the cell to the ends of the axon and back. A protein called tau stabilizes the
microtubules when phosphorylated and is therefore called a microtubule-associated protein. In
AD, tau undergoes hyperphosphorylation.
The hyperphosphorylated tau protein begins to pair with other threads, creating neurofibrillary
tangles, thus disintegrating the neuron's transport system.
Figure-1 -showing amyloid plaques and neurofibrillary tangles in Alzheimer's disease.

3. AD is also associated with decreased cerebral cortical levels of several proteins and
neurotransmitters, especially acetylcholine. There is a reduction in norepinephrine levels in
brain stem nuclei. Accumulation of aggregated amyloid fibrils, which are believed to be the
toxic form of the protein responsible for disrupting the cell's calcium ion homeostasis, induces
programmed cell death (apoptosis). Aβ selectively builds up in the mitochondria in the cells of
Alzheimer's-affected brains, and it also inhibits certain enzyme functions and the utilization of
glucose by neurons.
Alzheimer's disease is characterized by loss of neurons and synapses in the cerebral cortex and
certain subcortical regions. This loss results in gross atrophy of the affected regions, including
degeneration in the temporal lobe and parietal lobe, and parts of the frontal cortex and
cingulate gyrus (Figure 2).
Figure-2- Brain atrophy in Alzheimer’s disease
Inheritance
The vast majority of cases of Alzheimer's disease are sporadic, meaning that they are not
genetically inherited, although some genes may act as risk factors. On the other hand, around
0.1% of the cases are familial forms of Autosomal-dominant inheritance, which usually have an
onset before age 65.
Diagnosis
Alzheimer's disease is usually diagnosed clinically from the patient’s history, collateral history
from relatives, and clinical observations, based on the presence of characteristic neurological
and neuropsychological features and the absence of alternative conditions.
Assessment of intellectual functioning, including memory testing, can further characterize the
state of the disease.

4. Advanced medical imaging with computed tomography (CT) or magnetic resonance imaging
(MRI) can be used to help exclude other cerebral pathology or subtypes of dementia.
A histopathological confirmation, including a microscopic examination of brain tissue, is
required for a definitive diagnosis.
Treatment
There is no cure for Alzheimer's disease; available treatments offer relatively small
symptomatic benefit but remain palliative in nature. Current treatments can be
pharmaceutical, psychosocial, and caregiving. Four medications are approved by the U.S. Food
and Drug Administration to treat AD. Donepezil, rivastigmine, and galantamine) are used to
treat mild to moderate AD (Donepezil can be used for severe AD). Memantine is used to treat
moderate to severe AD. These drugs work by regulating neurotransmitters. They may help
maintain thinking, memory, and speaking skills and help with some behavioral issues. However,
these drugs don’t change the underlying disease process and may help only for a few months to
a few years.
Prion’s diseases
Prions diseases are a group of neurodegenerative disorders that can affect both humans and
animals. In humans, these conditions impair brain function, causing changes in memory,
personality, and behavior; a decline in intellectual function (dementia); and abnormal
movements, particularly difficulty coordinating movements (ataxia). The signs and symptoms of
prion disease typically begin in adulthood and worsen with time, leading to death within a few
months to several years. The most common form of prion disease that affects humans is
Creutzfeldt-Jakob disease (CJD). Prion diseases are very rare; approximately 350 cases are
reported in the USA every year.
Biochemical defect- A prion is a protein type that can trigger normal proteins (PrPC)in the brain
to fold abnormally. The normal function of this protein is unknown. The prion protein binds
with a normal protein to alter its structure and thus functions. Misfolded proteins ((PrPSc)
accumulate to form clumps in the brain, damaging the brain cells. The damaged brain gives a
spongiform appearance under a microscope. Due to this characteristic, Prion disease is also
called “Spongiform encephalopathy” (figure 3)

5. A) B)
Figure-3- A) Showing the transformation of a normal protein to a Prion protein (PrPSc) and B)
Spongiform appearance of brain in Prion disease.
Prion disease can develop in three ways:
1. Genetic- Due to a mutation in the gene that codes for a normal protein (PrPC)
2. Acquired or sporadic - Exposure of a normal protein (PrPC) to external agents that cause its
misfolding.
For example, variant Creutzfeldt-Jakob disease (vCJD) is a type of acquired prion disease in
humans that results from eating beef products containing PrPSc from cattle with prion disease.
In cows, this form of the disease is known as bovine spongiform encephalopathy (BSE) or, more
commonly, "mad cow disease." Another example of an acquired human prion disease is kuru,
which was identified in the South Fore population in Papua New Guinea. The disorder was
transmitted when individuals ate affected human tissue during cannibalistic funeral rituals.
Rarely, prion disease can be transmitted by accidental exposure to PrPSc-contaminated tissues
during a medical procedure. This type of prion disease, which accounts for 1 to 2 percent of all
cases, is classified as iatrogenic.
Symptoms- Symptoms of prion diseases include:
• Rapidly developing dementia
• Difficulty walking and changes in gait
• Hallucinations
• Muscle stiffness
• Confusion
• Fatigue
• Difficulty speaking

6. Diagnosis
• Prion diseases can only be confirmed by taking a sample of brain tissue during a biopsy
or after death. Other tests include:
• MRI scans of the brain; Samples of fluid from the spinal cord (spinal tap)
• Electroencephalogram, which analyzes brain waves; this painless test requires placing
electrodes on the scalp.
• Neurologic and visual examinations to evaluate for nerve damage and vision loss
Treatment
Prion diseases can't be cured, but certain medications may help slow their progress. Medical
management focuses on keeping people with these diseases as safe and comfortable as
possible despite progressive and debilitating symptoms.