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 ageing 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.

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.

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.

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 (PrP^C) 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 ((PrP^Sc) 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)

A)

 

Figure-3- A) Showing the transformation of a normal protein to a Prion protein (PrP^Sc) 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 (PrP^C)
2. Acquired or sporadic – Exposure of a normal protein (PrP^C) 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

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.