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Alzheimerdisease and apoptosis
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Alzheimerdisease and apoptosis



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  • 1. Under supervision of: Prof. Dr. Seham Abo Shosha Presented by: Sara Ahmed Youssry
  • 2. Alzheimer's disease (AD) Is a slowly progressive disease of the brain that is characterized by impairment of memory and eventually by disturbances in planning, language, and perception. Results from an increase in the production or accumulation of a specific protein (beta-amyloid protein) in the brain that leads to nerve cell death. Epidemiology The likelihood of having Alzheimer's disease increases after the age of 70 and may affect around 50% of persons over the age of 85. However, Alzheimer's disease is not a normal part of aging.
  • 3. Risk factors : •Increased age. The biggest risk factor for Alzheimer's disease •Genetic risk factors -The best-studied "risk" gene is the one that encodes apolipoprotein E (apoE). The apoE4 form of the gene has been associated with increased risk of Alzheimer's disease. Persons with one copy of the E4 gene usually have 2-3fold increased risk. Persons with two copies of the E4 gene have about 9-fold increase in risk. -Mutations in one of three genes: those encoding amyloid precursor protein (APP) and presenilins 1 and 2
  • 4. •Traumatic head injuries earlier in life, particularly among those with the apoE 4 gene. •limited formal education usually less than eight years . It is not known whether this reflects a decreased "cognitive reserve" or other factors associated with a lower educational level. •women have a higher risk for Alzheimer's disease than men. -women live longer than men -The role of estrogen in Alzheimer's disease remains an area of research focus.
  • 5. Symptoms of Alzheimer's disease The course of Alzheimer's disease is not the same in every person, but symptoms seem to develop over 3 stages. Very early signs and symptoms Memory problems are typically one of the first signs of AD. A) Mild Alzheimer's disease As the disease progresses, memory loss worsens, and changes in other cognitive abilities are evident. Problems can include: Getting lost Trouble handling money and paying bills Repeating questions Poor judgment Mood and personality changes Alzheimer's disease is often diagnosed at this stage
  • 6. B) Moderate Alzheimer's disease In this stage, damage occurs in areas of the brain that control language, reasoning, sensory processing, and conscious thought. Symptoms may include: Increased memory loss and confusion problems recognizing family and friends inability to learn new things Hallucinations. impulsive behavior C) Severe Alzheimer's disease People with severe Alzheimer's are completely dependent on others for their care. Near the end, the person may be in bed most or all of the time. Their symptoms often include: Inability to communicate Weight loss Skin infections Difficulty swallowing Increased sleeping lack of control of bowel and bladder
  • 7. What causes Alzheimer's disease? It is a neurodegenerative disease, caused by progressive brain cell death that happens over a course of time. The total brain size shrinks with Alzheimer's - the tissue has progressively fewer nerve cells and connections.
  • 8. Postmortem/autopsy will always show tiny inclusions in the nerve tissue, called plaques and tangles: •Plaques are found between the dying cells in the brain - from the build-up of a protein called beta-amyloid (amyloid plaques). •The tangles are within the brain neurons - from a disintegration of another protein, called tau.
  • 9. Several competing hypotheses exist trying to explain the cause of the disease: -Genetics:( Amyloid hypothesis ) : The most important one Mutations in one of three genes: those encoding amyloid precursor protein (APP) and presenilins 1 and 2 increase the production of a small protein called AB42, which is the main component of senile plaques ( Familial type of AD ) APOE4, is a major genetic risk factor for AD leading to excess amyloid buildup in the brain ( Sporadic type of AD )
  • 10. Tau hypothesis Tau protein abnormalities initiate the disease cascade. Hyperphosphorylated tau begins to pair with other threads of tau. Eventually, they form neurofibrillary tangles inside nerve cell bodies. When this occurs, the microtubules disintegrate, collapsing the neuron's transport system. This may result first in malfunctions in communication between neurons and later in the death of the cells Other hypotheses -Age-related myelin breakdown in the brain. Iron released during myelin breakdown cause further damage. Homeostatic myelin repair processes contribute to the development of proteinaceous deposits such as beta-amyloid and tau. -Oxidative stress may be significant in the formation of the pathology
  • 11. Mechanisms linking AD pathogenesis to apoptosis. The amyloid hypothesis points to the accumulation of betaamyloid peptides ( the toxic form of the protein ) as the central event triggering neuron degeneration “cascade” that results in neuron death (apoptosis) and cognitive impairments Aß has been shown to destabilize neuronal calcium homeostasis, generally leading to an increase in cytosolic calcium which can then trigger neuronal apoptosis Aß resulted in increased p53 levels, which were sufficient to increase Bax protein and nuclear fragmentation In vitro Aß induces expression of pro-apoptotic Bcl-2 proteins, including Bax, and down regulation of anti-apoptotic members such as Bcl-2, Bcl-xL and Bcl-w.
  • 12. Aβ associated mitochondrial dysfunction leading to cognitive decline in AD: •Decreased mitochondrial motility resulting in disorganized synaptic mitochondrial distribution •Decreased mitochondrial ATP provision and respiratory function •Decreased cytochrome oxidase activity •Elevated mitochondria-associated oxidative stress •Increased mitochondrial permeability •Decreased mitochondrial Ca2+ modulating capacity and Ca2+ accumulation •Release of pro-apoptogenic factors from mitochondria •Membrane potential collapse •Increased free radical production Increased mitochondrial fragmentation (important event early in apoptosis
  • 13. Aβ can have toxic effects via direct and indirect mechanisms including inducing local inflammation. Eg. interleukins (IL), TNFα, and TNFβ Increased amounts of cell injury or death of neurons can occur when the inflammatory response is chronic and uncontrolled in nature Impact of tau on toxicity, that tau becomes more hyperphosphorylated with disease progression and leads to greater dendritic toxicity.
  • 14. In particular, FasL appears to play an important role in Aβmediated neurotoxicity. Exposure of cortical neurons to Aß activates c-Jun N-terminal kinase (JNK). JNK is required for the activation of the c-Jun transcription factor, which in turn stimulates the transcription of several key target genes, including the death inducer FasL. The binding of FasL to its receptor Fas then induces a cascade of events, leading to caspase activation and, ultimately, apoptosis . In parallel, tumor necrosis factor alpha (TNF ), tumor necrosis factor receptor 1 (TNF-R1) and TNF-R1-associated death domain protein (TRADD) have all been found to be increased in AD.
  • 15.  Alterations in the distribution of different neurotrophic factors and in the expression of their receptors such as the brain derived neurotrophic factor (BDNF) have been described in AD Initiate apoptosis
  • 16. How is AD Diagnosed? •Asking questions about the person’s general health, any past medical problems, and the ability to do daily activities •Memory tests, problem solving strategies, attention, counting •Tests of blood, urine, or spinal fluid •Brain scans Computed tomography (CT) or magnetic resonance imaging (MRI) of the brain. In the early stages of dementia, brain image scans may be normal. In later stages, an MRI may show a decrease in the size of different areas of the brain. While the scans do not confirm the diagnosis of AD, they do exclude other causes of dementia (such as stroke and tumor). However, the only way to know for certain that someone has AD is to examine a sample of their brain tissue after death.
  • 17. Treatment There is no cure for AD. The goals of treatment are: -Slow the progression of the disease. -Manage symptoms, such as behavior problems, confusion, and sleep problems -Change home environment so you can better perform daily activities -Support family members and other caregivers a) DRUG TREATMENT Medicines are used to help slow down the rate at which symptoms become worse. The benefit from these drugs is usually small. Modulate neurotransmitters, either acetylcholine or glutamate. (reduction in the activity of cholinergic neurons is a feature of AD). Eg.cholinesterase inhibitors (ChEIs) and a partial N-methyl-D-aspartate (NMDA) antagonist.
  • 18. Psychotropic medications have been used to treat behavioral symptoms: -Antidepressants -Anxiolytics -Antiparkinsonian agents -Beta-blockers -Antiepileptic drugs (for their effects on behavior) -Neuroleptics b) Potential surgical treatments in the future may include the use of devices to infuse neurotrophic factors, such as growth factors, to palliate AD. c) If the patient becomes a danger to him/herself or others, shortterm hospitalization may be indicated