Absence of amyloid β oligomers at the postsynapse and regulated synaptic Zn2+ in cognitively intact aged individuals with Alzheimer’s disease neuropathology

Early cognitive impairment in Alzheimer Disease (AD) is thought to result from the dysfunctional effect of amyloid beta (Aβ) oligomers targeting the synapses. Some individuals, however, escape cognitive decline despite the presence of the neuropathologic features of AD (Aβ plaques and neurofibrillary tangles). We term this group Non-Demented with AD Neuropathology or NDAN. The present study illustrates one putative resistance mechanism involved in NDAN cases which may suggest targets for the effective treatment of AD. Here we describe the localization of Aβ oligomers at the postsynapse in hippocampi from AD cases. Notably, however, we also found that while present in soluble fractions, Aβ oligomers are absent from hippocampal postsynapses in NDAN cases. In addition, levels of phosphorylated (active) CREB, a transcription factor important for synaptic plasticity, are normal in NDAN individuals, suggesting that their synapses are functionally intact. Analysis of Zn2+ showed that levels were increased in both soluble fractions and synaptic vesicles in AD hippocampi, paralleled by a decrease of expression of the synaptic vesicle Zn2+ transporter, ZnT3. Conversely, in NDAN individuals, levels of Zn2+ in soluble fractions were significantly lower than in AD, whereas in synaptic vesicles the levels of Zn2+ were similar to AD, but accompanied by preserved expression of the ZnT3. Taken together, these data illustrate that despite substantial AD neuropathology, Aβ oligomers, and increased synaptic vesicle Zn2+, susceptible brain tissue in these aged NDAN individuals features, as compared to symptomatic AD subjects, significantly lower total Zn2+ levels and no association of Aβ oligomers with the postsynapse, which collectively may promote the maintenance of intact cognitive function.


FEB 21, 23
Other factors involved in AD The role of tau. APOE4 is a late-onset gene and carries a risk of developing AD. The blood brain barrier may play a role and interact with APOE4. Decoding Darkness. Aging with Grace, Chapter 8. Small and Duff, 2008;Yu et al. 2014. (Zlokovic) FEB 28, MAR 2 . AD may begin much earlier than we thought. The essays in Aging with Grace, chapter 7. Imaging studies. The default network is altered early in AD. Buckner et al, 2008;Dean et al., 2014.

FEB 28 End of unrestricted withdrawal period. (get a W on transcript, but does not affect GPA)
MAR 7,9 Review, Animal models: Mice are useful.Transgenic mice have been used to model AD. They can be used to assess treatments and understand factors influencing the progress of the disease. Behavioral measures of memory loss; spatial memory, passive avoidance. Memory loss is seen before plaques appear. This may be due to soluble amyloid. Review. Hsiao et al., 1996. (

APR 4,6 Prescription Drugs and other treatments for AD ;
AChE inhibitors, most AD drugs target acetylcholine degradation. Memantine targets a glutamate receptor. A new drug, aducanumab (Aduhelm), has been approved for the first time in 18 years. Lecanemab (Leqembi) has also been approved. Antibody treatment may be effective. Anti-cholesterol drugs, young blood transfusion are alternative approaches. ALZTALK on Aducanumab Ballard et al., 2005;Middeldorp et al, 2016;Parsons et al., 2007;Villeda et al., 2011;Zhao et al., Y,. 2020. APR 11,13 Treatments continued. Role of metals in AD. Possible role of the metals in AD. The plaques are high in iron, copper, zinc, and (?) aluminium. Zinc can cause memory loss, but this may be due to an induced copper deficit. Behavioral and histological data in normal and Tg mice. Zinc is prescribed for age-related macular degeneration, but could impact circadian rhythms. Copper with cholesterol may be a risk factor. Iron may be dangerous. Drugs acting as Metal ionophores; PBT2 is a possible remedy for AD. APR 20, 27 Preventative factors. The rate of AD is going down, which may be due to healthier life styles. Exercise, education, sleep, and music, etc. are helpful. Diet can include foods with folic acid, caffeine and those that act as anti oxidants: dark chocolate, spinach, blueberries, curcumin, pomegranates. Brushing your teeth is important! Student presentations Adlard et al., 2005;Drew, 2014;Ide, 2016;Mathews et al., 2013;Tergesen, 2019Underwood. 2013Xie et al., 2013,. (Nedergaard is the senior author. )

PAPERS DUE April 21 FINAL EXAM DUE APRIL 26 TH (take home)
There will be a take home quiz most weeks on one or more of the papers assigned for that week. The papers will normally be posted on Blackboard. The exams will be short answers with an essay; students may bring a one page summery to the exam. Undergraduate and MA students can work together for the presentation, a paper based on the same subject as the presentation is also required. Papers must be written independently. Because exercise has been shown to be the best way to reduce cognitive impairment there will be a short exercise break in the middle of each class.

Honor Code
George Mason University has an Honor Code, which requires all members of this community to maintain the highest standards of academic honesty and integrity. Cheating, plagiarism, lying, and stealing are all prohibited. It is every student's responsibility to familiarize himself or herself with the Honor Code. The Honor Code is available at: http://oai.gmu.edu/the-mason-honor-code-2/ All violations of the Honor Code will be reported to the Honor Committee.
Papers and take home exams will be scanned for AI or plagiarism.

Communications via GMU E-mail:
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Technology
Quizzes will be posted on Blackboard. Dr Flinn and the TA will also communicate with students in the class via e mail.
Cell phones may not be used in class. Students may use computers to take class notes but for no other purpose.

Class Cancellation
If class has to be cancelled, an e mail will be sent to the class.