NE102 Lecture Notes 3

Which hypothesis is more important tau or amyloid is

Info icon This preview shows pages 33–36. Sign up to view the full content.

View Full Document Right Arrow Icon
OBVIOUS QUESTION: What causes synapse loss & neurodegeneration in AD? Which hypothesis is more important, tau or amyloid? Is it A /plaques? Is it tau/tangles? Both? Neither? β Most powerful evidence comes from genetic studies on families with a very rare  inherited form of AD NOTE:  Vast majority (95-99%) of AD cases are “sporadic” and with onset of symptoms in  individuals ~80+ years of age Sporadic AD or Late-onset AD (LOAD) An inherited form of AD exists (1-5% of cases) with onset of symptoms as early as 35- 40 years of age Familiar AD (FAD) or Early-onset AD Development of FAD is due to the inheritance of particular  low frequency genetic  alleles  – referred to as genetic mutations FAMILIAL ALZHEIMER DIESEASE
Image of page 33

Info iconThis preview has intentionally blurred sections. Sign up to view the full version.

View Full Document Right Arrow Icon
Finding the Molecular cause of AD pt. 2 18:04 AD researchers studied the genetics of families with FAD to investigate the cause of  their disease Sweden, London, Belgium, Florida Started with a pedigree analysis A method to depict the inheritance of phenotype & genotype as  pedigree charts  Inheritance of a phenotype is often depicted by shading Inheritance of genotype is depicted beneath each individual  Next step: Identify gene alleles/mutations responsible for the phenotype Assumption: Inheritance of specific genetic mutations causes the observed FAD NEXT CHALLENGE: Identify the specific mutations/alleles responsible for AD in these  individuals All within APP – All affect APP cleavage APP mutations linked with FAD Swedish mutations: increased  -cleavage (increase in A  production) β β Flemish mutations: decreased  -cleavage  α Florida and London mutations: increased  ϒ 42 cleavage = more A 42 production β NOTE:  ϒ -secretase cleavage specificity varies, which generates A 40 or A 42 β β A 42 demonstrates a far greater propensity to aggregate – more A 42 = worse it is β β Mutations in Presenilin 1 & 2 also cause FAD Presenilin = the catalytic subunit the cleaves APP-CTFs Causes alteration of  ϒ -secretase cleavage site = more A 42 β Down’s syndrome Increased APP production = more A 40 & A 42 β β
Image of page 34
Finding the Molecular cause of AD pt. 2 18:04 Caused by inheritance of THREE Copies of chromosome 21 APP gene is on chromosome 21 – Down’s patients have 3 copies of APP gene Down’s patients that LACK the triplication of APP gene do NOT develop AD-associated  cognitive decline or pathology AMYLOID CASCADE HYPOTHESIS Cause – A  peptide accumulation (& oligomerization) – plaques - neuronal injury – β   neuronal dysfunction and death – dementia TRANSGENIC MOUSE MODELS Cell culture studies are key to our current & developing understanding of AD Limitations of cell culture They don’t establish “physiological relevance Cannot study the consequences o these events on more complex brain function QUESTION: How can we study the molecular events underlying AD & their effects  within an intact brain/organism?
Image of page 35

Info iconThis preview has intentionally blurred sections. Sign up to view the full version.

View Full Document Right Arrow Icon
Image of page 36
This is the end of the preview. Sign up to access the rest of the document.

{[ snackBarMessage ]}

What students are saying

  • Left Quote Icon

    As a current student on this bumpy collegiate pathway, I stumbled upon Course Hero, where I can find study resources for nearly all my courses, get online help from tutors 24/7, and even share my old projects, papers, and lecture notes with other students.

    Student Picture

    Kiran Temple University Fox School of Business ‘17, Course Hero Intern

  • Left Quote Icon

    I cannot even describe how much Course Hero helped me this summer. It’s truly become something I can always rely on and help me. In the end, I was not only able to survive summer classes, but I was able to thrive thanks to Course Hero.

    Student Picture

    Dana University of Pennsylvania ‘17, Course Hero Intern

  • Left Quote Icon

    The ability to access any university’s resources through Course Hero proved invaluable in my case. I was behind on Tulane coursework and actually used UCLA’s materials to help me move forward and get everything together on time.

    Student Picture

    Jill Tulane University ‘16, Course Hero Intern