1、Alzheimers Disease: Genetics, Pathogenesis, Models, and Experimental Therapeutics,Auguste Deter, Alois Alzheimers patient in November 1901, first described patient withAlzheimers Disease.,1864 - Dr. Alois Alzheimer, psychiatrist, pathologist, born in Marktbreit, Bavaria,Causes of dementia,Definition
2、s,Dementia a general term for a group of disorders that cause irreversible cognitive decline as a result of biological damage to brain cellsAlzheimers disease (AD) the most common dementia, accounting for 50-70 percent of cases Other forms of dementia include Vascular dementia Parkinsons disease Dem
3、entia with Lewy bodies Frontotemporal dementia Creutzfeldt-Jakob disease Normal pressure hydrocephalus Alzheimers disease = Alzheimers disease and related dementias,Clinical features and Laboratory studies,Alzheimer disease (AD) is the most common form of dementia and usually occurs in old age. It i
4、s invariably fatal, generally within ten years of the first signs. Normal aging involves forgetfulness but the early signs of AD include unusual memory loss.(remembering recent events and the names of people and things) As the disease progresses the patient exhibits more serious problems.(subject to
5、 mood swings and unable to perform complex activities such as driving.)In the latter stages they forget how to do simple things and then require full-time care.,Neuropathorogy and Biochemistry of AD,NeuropathologyAlzheimers disease is characterised by loss of neurons and synapses in the cerebral cor
6、tex and certain subcortical regions. This loss results in degeneration in the temporal lobe and parietal lobe, and parts of the frontal cortex. Reductions in the size of specific brain regions in patients as they progressed from mild cognitive impairment to Alzheimers disease.,Both amyloid plaques a
7、nd neurofibrillary tangles are clearly visible by microscopy in brains of those afflicted by AD. Plaques are dense, mostly insoluble deposits of amyloid-beta peptide and cellular material outside and around neurons. Tangles (neurofibrillary tangles) are aggregates of the microtubule-associated prote
8、in tau which has become hyperphosphorylated and accumulate inside the cells themselves.,BiochemistryEnzymes act on the APP (amyloid precursor protein) and cut it into fragments. The beta-amyloid fragment is crucial in the formation of senile plaques in AD.AD has been identified as a protein misfoldi
9、ng disease, caused by accumulation of abnormally folded A-beta and tau proteins in the brain. Plaques are made up of small peptides, 3943 amino acids, called beta-amyloid (also written as A-beta or A). fragment from a larger protein called APP, a transmembrane protein that penetrates through the neu
10、rons membrane. (APP: neuron growth, survival and post-injury repair),Neuropathorogy and Biochemistry of AD,BiochemistryIn Alzheimers disease, an abnormal aggregation of the tau protein lead to the disintegration of microtubules in brain cells.Tau protein(microtubule-associated protein) stabilizes th
11、e microtubules when phosphorylated. In AD, tau becoming hyperphosphorylated; creating neurofibrillary tangles and disintegrating the neurons transport system.,Neuropathorogy and Biochemistry of AD,Genetic: Familial AD and risk factors,The majority of cases of Alzheimers disease are sporadic not gene
12、tically inherited although some genes may act as risk factors around 0.1% of the cases are familial forms of autosomal-dominant inheritanceAutosomal dominant familial AD can be attributed to mutations in one of three genes: amyloid precursor protein (APP) and presenilins 1 and 2. Mutations in the AP
13、P and presenilin genes increase the production of a A42.The best known genetic risk factor is the inheritance of the 4 allele of the apolipoprotein E (APOE). Between 40 and 80% of patients with AD possess at least one apoE4 allele. Therefore the APOE4 allele increases the risk of the disease.,APP an
14、d PS families of proteins,Familial Alzheimer disease is caused by mutations in at least 3 genes:PSEN1 - Presenilin 1 (PSEN1 located on chromosome 14) Mutations in this gene cause familial Alzheimers type under 50 years old. This protein has been identified as part of the enzymatic complex that cleav
15、es amyloid beta peptide from APP.PSEN2 - Presenilin 2 (PSEN2 located on chromosome 1) The presenilin 2 gene is very similar in structure and function to PSEN1. APP Amyloid beta (A4) precursor proteinProcessing of the amyloid precursor protein Mutations to the amyloid beta A4 precursor protein (APP)
16、located on the long arm of chromosome 21 causes familial Alzheimer disease.,SecretaseBACE1 -amyloid cleaving enzyme1 This transmembrane aspartyl protease is directlly involved in the cleavage of APP at the sites of A in APP.-secretase This multiprotein catalytic complex includes PS1 and PS2; nicastr
17、in (Nct), a type 1 transmembrane glycoprotein; and Aph-1 and Pen-2, two multipass transmembrane protein.,APP and PS families of proteins,Processing of APP by secretases,Genetic models of A amyloidosis and AD-linked taupathies,A amyloidosisAmyloid beta is a peptide of 39-43 amino acids Main constitue
18、nt of amyloid plaques in the brains of Alzheimers disease patients. A is proteolytically derived from a larger integral membrane protein, the amyloid precursor protein (APP).AD-linked taupathiesTaupathies are a class of neurodegenerative diseases resulting from the pathological aggregation of tau pr
19、otein in so-called neurofibrillary tangles (NFT) in the human brain.,Targeting of genes encoding amyloidogenic secretases,To understand the function of some of the proteins thought to have roles in AD: targeted a variety of genes including BACE1, PS1, Nct, and Aph-1.BACE1-/- Mice BACE1 is a key enzy
20、me in the generation of the A peptide that plays a central role in the pathogenesis of Alzheimers disease. PS1-/- Mice PS1 knock-in mice exhibited NFT-like tau pathology in the absence of A deposition. PS1 mutations contribute to the onset of AD not only by enhancing A142 production but by also proc
21、essing that lead to neurodegeneration.,Clinical approaches to Alzheimers Disease,Cholinesterase Inhibitor Tacrine, Donepezil, Rivastigminne, GalantamineNMDA Antagonists Glutamate NMDA Memanitn- and -secretase Inhibition and -secretase Modulation Toxic peptide A42 -secretase Flurizan,Conclusions,It i
22、s anticipated that discoveries during the next few year will lead to the design of new mechanism-based therapies that can be tested in animal models, and, eventually, these approaches will be introduced successfully into the clinic for the benefit of patients with this devastating illness.,Thank you,Referance,http:/ disease. (Castellani RJ et al., 2010)Alzheimers disease neurofibrillary degeneration: pivotal and multifactorial. (qbal K et al., 2010),
