Alzheimer’s Disease (AD)

Alzheimer’s Disease? Alzheimer's disease (AD), also known as Senile Dementia of the Alzheimer Type (SDAT) or simply Alzheimer’s is the most common form of dementia. This incurable, degenerative, terminal disease was first described by a German psychiatrist and neuropathologist Alois Alzheimer in 1906 and was named after him. Alzheimer's disease (AD) is a slowly progressive neurodegenerative disorder of the brain mostly affects the elderly and characterized by impairment of memory and eventually by disturbances in reasoning, planning, language, and perception. Many scientists believe that Alzheimer's disease 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. Generally, it is diagnosed in people over 65 years of age.

AD Signs & Symptoms: Confirmation of Diagnosis: Memory loss for recent events or new information. Progresses into dementia  almost total memory loss Inability to converse, loss of language ability Confirmation of Diagnosis: Neuronal (amyloid, b amyloid protein, Ab amyloid) plaques Neurofibrillary tangles Brain Atrophy, Brain shrinkage (loss of neurons mainly in the hippocampus and basal forebrain)

Stages of AD

Brain Atrophy in AD WRONG! http://abdellab.sunderland.ac.uk/lectures/Neurodegeneration/References/Brain_Neurons_AD_Normal.html

The Anatomical Hallmark of Alzheimer’s Pathology: Amyloid Plaques and Neurofibrillary Tangles in Brain Amyloid Plaques contain large amounts of a 42 amino acid peptide termed “b-amyloid”, or Ab42 b-amyloid itself is the initial cause of the pathophysiology that leads to dementia. Neurofibrillary tangles: rich in cytoskeletal proteins, especially the microtubule-associated protein, “tau”. In the tangles: heavily phosphorylated proteins, which may cause aggregation and precipitation of the cytoskeleton. Also generally reduced brain volume, especially in entorhinal cortex and hippocampus From http://www.rnw.nl/health/html/brain.html

Structure of amyloid precursor protein (APP)

Unsoluble, aggregates into plaques b-secretase Pathway: (not drawn to scale) b a g APP Protein: (1) b-secretase cuts APP protein, giving: (2) g-secretase cuts this residue, giving: or Ab40 Fragment Soluble Ab42 Fragment Unsoluble, aggregates into plaques

Amyloid precursor protein (APP) is membrane protein that sits in the membrane and extends outward. It is though to be important for neuronal growth, survival, and repair. From: www.niapublications.org/pubs/unraveling/01.htm

Enzymes cut the APP into fragments, the most important of which for AD is called b-amyloid (beta-amyloid) or Ab. From: www.niapublications.org/pubs/unraveling/01.htm

Beta-amyloid is “sticky” so the fragments cling together along with other material outside of the cell, forming the plaques seen in the AD brain. From: www.niapublications.org/pubs/unraveling/01.htm

Processing of APP

Two Major Hypotheses for AD: b amyloid protein (BAP) v. tau BAPtists: The accumulation of a fragment of the amyloid precursor protein or APP (the amyloid beta 42 residue fragment or Ab-42) leads to the formation of plaques that kill neurons. TAUists: Abnormal phosphorylation of tau proteins makes them “sticky,” leading to the break up of microtubules. The resulting loss of axonal transport causes cell death.

Amyloid Hypothesis (it’s the plaques) The amyloid precursor protein (APP) is broken down by a series of secretases (see previous two slides). During this process, a nonsoluble fragment of the APP protein (called Ab-42) accumulates and is deposited outside the cell. The nonsoluble or “sticky” nature of Ab-42 helps other protein fragments (including apoE) to gather into plaques. Somehow the plaques (or possible the migration of Ab-42 outside the cell) cause neuronal death. PSEN1 & PSEN2 genes  subunits of g secretase.

Theories of How Damage Occurs in AD From Inside the Cell: Tangle Formation undergo abnormal chemical changes and assemble into spirals called paired helical filaments... Axon Paired Helical Filament Dendrites Neuron Tangles thus creating tangles that disrupt cell functions and lead to cell death. Microtubules Tau Proteins Tau proteins, which normally stabilize microtubules in brain cells... Janssen PCP Core T1 Syllabus WO: 2749 Sources: Dr John Trojanowski and Dr Virginia M. Y. Lee. University of Pennsylvania Medical Center.

Microtubules are like railroad tracks that transport nutrition and other molecules. Tau-proteins act as “ties” that stabilize the structure of the microtubules. In AD, tau proteins become tangled, unstabilizing the structure of the microtubule. Loss of axonal transport results in cell death.

Loss of cholinergic neurons in the basal forebrain nuclei; therefore, restoring cholinergic function might be helpful. Choline acetyltransferase (CAT) activity is reduced in cortex and hippocampus. Nicotinic, but not muscarinic, receptors are reduced.

Therapeutic approaches Cholinesterase inhibitors: The first drugs approved for treating AD. Enhancement of cholinergic transmission might compensate for the cholinergic deficit. Improve cognitive performance. Inhibiting excitotoxicity Inhibiting neurodegeneration (future target).

Cholinesterase inhibitors Tacrine The first drug approved for treating AD. Four times daily Cholinergic side effects (nausea and abdominal cramps) Hepatotoxicity

Cholinesterase inhibitors Donepezil (no hepatotoxicity) Rivastigmine: Long-lasting drug, CNS selective (fewer peripheral cholinergic side effects). Galantamine: Acts partly by cholinesterase inhibitor and partly by activation of brain nicotinic AChRs.

Inhibiting excitotoxicity Memantine a use-dependent blockade of NMDA receptors.  

Additional Treatments for AD Role of dietary factors Low saturated fat diets, Vitamin E – decrease cytotoxicity - may slow the progression of the disease Cholinergic stimulation: Nicotine patch, varenicline (Chantix)

Pharmacologic Options for AD Cognitive enhancers; can improve cognition and functional ability 2 classes Cholinesterase inhibitors (ChEIs) NMDA-receptor antagonist Cholinesterase inhibitors delay the breakdown of acetylcholine released into synaptic clefts and so enhance cholinergic neurotransmission Memantine may prevent excitatory neurotoxicity by binding to the NMDA receptor and normalizing the influx of magnesium and calcium into the synapse???

Treatment of AD: Cognitive Enhancers Drug Name  Dosage form Indication Donepezil (Aricept) Tablet, orally disintegrating table Mild to severe Galantamine (Razadyne®) Tablet/oral solution Extended-release capsule* Mild to moderate Rivastigmine (Exelon®) Capsule Patch Memantine (Namenda®) Tablet*, oral solution* Mod to severe Cholinesterase inhibitors - Despite the slight variations in the mode of action of the three cholinesterase inhibitors there is no evidence of any differences between them with respect to efficacy. The evidence from one large trial shows fewer adverse events associated with donepezil compared with rivastigmine. [Birks 2006] For best results, these medications should be titrated to the highest tolerated dose. Alternative dosage forms may improve compliance. product information Aricept. Woodcliff Lake, NJ: Eisai Corp; 2010. Razadyne. Titusville, NJ: Ortho-McNeil Neurologics; 2011. Exelon. East Hanover, NJ; Novartis Corp; 2009.

NMDA-receptor antagonist Common Side Effects Cholinesterase inhibitors (ChEIs) (Donepezil, galantamine, rivastigmine) NMDA-receptor antagonist (Memantine) Nausea Vomiting Diarrhea Weight loss Loss of appetite Muscle weakness Dizziness Headache Constipation Confusion ChEIs The most common reason for discontinuing a ChEI is gastrointestinal disturbances, such as nausea, vomiting and diarrhea that may result in anorexia and weight loss. Cardiovascular side effects include dizziness, syncope and bradycardia Incontinence, leg cramps and sleep disturbances also may occur. Side effects associated with cholinesterase inhibitors occur primarily during the dose-escalation phase of therapy and seem to be transient. If patient is not tolerating a cholinesterase inhibitors, switching to another agent may minimize side effects. National Institute on Aging. Alzheimer’s disease medications. November 2008. NIH Publication No. 08-3431. Available at: http://www.nia.nih.gov/Alzheimers/Publications/medicationsfs.htm. Accessed July 24, 2009.

Current theory: Multifactorial, involving several pathways. Protein accumulation:  plaques & tangles Inflammation: Unregulated activation of glia Lipid distribution: Lipid membrane site of APP cleavage.

Targets for Future Therapies -secretase inhibitors -secretase inhibitors Monoclonal antibodies Tau protein Inflammation Insulin resistance Beta-amyloid is the chief component of plaques, one hallmark Alzheimer's brain abnormality. We now have a detailed understanding of how this protein fragment is clipped from its parent compound amyloid precursor protein (APP) by two enzymes — beta-secretase and gamma-secretase. Researchers are developing medications aimed at virtually every point in amyloid processing. This includes blocking activity of both enzymes; preventing the beta-amyloid fragments from clumping into plaques; and even using antibodies against beta-amyloid to clear it from the brain.  Tau protein is the chief component of tangles, the other hallmark brain abnormality. Researchers are investigating strategies to keep tau molecules from collapsing and twisting into tangles, a process that destroys a vital cell transport system. Inflammation is another key Alzheimer's brain abnormality. We’ve learned a great deal about molecules involved in the body's overall inflammatory response and are working to better understand specific aspects of inflammation most active in the brain. These insights may point to novel anti-inflammatory treatments for Alzheimer's disease. Insulin resistance and the way neurons process insulin may be linked to Alzheimer's disease. Researchers are exploring the role of insulin in the brain and closely related questions of how neurons use glucose. These investigations may reveal strategies to support cell function and stave off Alzheimer-related changes.

Inhibiting neurodegeneration (clinical trials) Phase II/ Phase III Inhibitors of Ab aggregation (Immunological approach; antibody directed against Ab). Inhibitors of b- and g-secretase. Immunological approach (antibody directed against Ab). Aβ vaccination Statins: HMG-CaA reductase inhibitors

Inhibiting neurodegeneration (clinical trials) Phase II/ Phase III Clioquinol (amoebicidal & metal chelating agent): Ab plaques bind cooper and zinc, thus removal of these metal ions promotes dissolution of the plaques. NGF (Nerve growth factor): shortage of growth factors may contribute to the loss of forebrain cholinergic neurons in Alzheimer’s disease. NSAIDs (esp. ibuprofen & indomethacin) reduce Ab42 formation by regulating g-secretase (unrelated to COX inhibition)