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Alzheimer's Afternoons Seminar Series Summaries

Insights and discussion from the cutting edge with reference to journal articles and other research papers.
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Re: Alzheimer's Afternoons Seminar Series Summaries

Postby Fiver » Wed Apr 22, 2020 9:06 am

Enhanced skeletal muscle as a novel determinant of CNS aging and Alzheimer’s disease
Alzheimer’s Afternoons Seminar Series (April 21)
Dr. Constanza J. Cortes, Brain Aging Physiology Lab, University of Alabama Birmingham

Takeaway: A robust lysosomal waste disposal system in muscle tissue promotes healthy cognition in aging mice and those predisposed to Alzheimer’s disease. The link seems to be the secretion of myokines by young, exercised muscle tissue, which circulates to the central nervous system and supports brain health.

Dr. Cortes is interested in how distant tissues effect brain aging and presented unpublished work for her seminar. She began by reminding us of the nine hallmarks of aging, described by:

López-Otín C, Blasco MA, Partridge L, Serrano M, Kroemer G. The hallmarks of aging. Cell. 2013;153(6):1194–1217. doi:10.1016/j.cell.2013.05.039 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3836174/ See figure 1.

She pointed out that seven of these nine marks of aging are involved in Alzheimer’s disease. Her interests focus on three: loss of proteostatis, deregulated nutrient sensing, and mitochondrial dysfunction. Here she will talk mainly about proteostasis.

Proteostatis, or “protein homeostasis”, involves all of protein metabolism, folding, cycling, degradation, and aggregation occurring in young, healthy cells and tissues – as described in Figure 3 of the article above. Dr. Cortes explained that aging causes a loss of proteostasis, such as decrease in production of protein chaperones and a decrease in appropriate protein degradation. This forces proteins into the “misfolding pathway”. The accumulation of protein inclusions can be observed, especially in neurons. This occurs in several neurodegenerative diseases, including Huntington’s, Parkinson’s, and Alzheimer’s disease.

She observed that altering (“tweeking”) proteostasis in one tissue of the body can have effects in other, distant tissues. This was first observed in simple model organisms, such as worms and fruit flies. The signal transmitting these effects was found to be insulin-like peptides.

Insulin-like peptides, also called insulin-like growth factors (IGFs), are proteins with high sequence similarity to insulin which cells use to communicate with one another and adapt to their environment.

Dr. Cortes mentioned that these peptides seem to support healthy proteostatis and are associated with longevity, at least in these simple model organisms.

What about in mammals? She reminded us that there are only two interventions known to delay aging phenotypes in all animals, including mammals: exercise and dietary restriction. While the exact mechanisms for these effects are unclear, both delay aging metabolic phenotypes, including the loss of proteostasis.

One particular tissue, skeletal muscle (SM), is especially influential in secreting these types of signals and helping to maintain body-wide proteostasis. Young, healthy, and active SM seems to benefit signaling via the mTOR, IIS, AMPK, PGC1α pathways, for example. An increase in muscle bioenergetics can be observed, and skeletal muscle autophagy is often improved. In short, SM acts as an endocrine organ; it secretes signals called myokines (skeletal muscle hormones) to communicate with other organs and organ systems, such as the liver, pancreas, and adipose tissues.

To test this link between muscles and other organs, especially the brain, Dr. Cortes focused on transcription factor EB (TFEB), which regulates lysosomal function and autophagy.

For those unfamiliar with this molecule:

Lysosomes are bubble-like organelles in the cell cytoplasm containing degradative enzymes. They are a part of the cell’s waste disposal system, whereby compounds taken up by endocytosis or autophagy are broken down.

TFEB is called “a master gene for lysosomal biogenesis”. It controls the production of lysosomal hydrolases, membrane proteins and genes involved in autophagy.

When the cell is starving or in certain diseased states, TFEB migrates from the cytoplasm to the nucleus, resulting in the activation of many target genes.

Higher TFEB production usually results in more lysosomes being produced and more autophagy.

When researchers “overexpress” TFEB overexpression in cells and mouse models of Huntington’s, Parkinson’s, and Alzheimer’s diseases, waste products are degraded the disease phenotypes are reduced.

Dr. Cortes pointed out that when wild-type mice are starved TFEB expression is increased in skeletal muscle. She wondered if this change in SM could benefit the brain.

First tests: +TFEB mice

To test this, she created a new mouse model which expressed the human TFEB gene “on demand”, but only in SM. This meant that TFEB protein levels would be 3-5x higher in the SM of these mice, when the system was triggered.

She finds that this seems to increase autophagy, or rather cellular markers of autophagy, by ~20-30%. The normal age-related problems seen in aging mice, including the presence of aggregated proteins in SM tissues, did not occur in these +TFEB mice.

An interesting note: Dr. Cortes pointed out that the protein aggregations and inclusions occurring in aging muscles also occur in skin cells, causing “age spots”.

In short, +TFEB mice had muscles that seemed younger; they looked like 6-month old muscles instead of 16-month old muscles (the difference between young adult and aged mice). It seems to prevent muscle aging.

Cell metabolism was altered as well. In SM tissues +TFEB mice had:

• higher levels of proteins involved, directly and indirectly, in mitochondrial oxidative phosphorylation (OXPHOS)
• larger mitochondria
• increased glucose processing and accumulation of glycogen
• Higher levels of many enzymes involved in glycolysis
• Improved OXPHOS capacity, which did not decrease with age (as it normally does)
• Some myokine levels were increased
• Some markers of inflammation (e.g., IL6) were reduced

What about the brain? Were any of these benefits occurring in CNS tissue?

Yes, even though the +TFEB gene was only expressed in SM, some similar changes were observed in the brains of 18 month old mice.

• Proteostasis proteins were more abundant.
• Increases in mitochondrial autophagy were observed.
• Improvements in lysosomal function – observed via the clearing of lipofuscin in lysosomes - were also noted.
• Cognition was also improved in these +TFEB mice. Performance in Barnes maze and novel object recognition tests were improved.

So, improved proteostasis in SM leads to better muscle health during aging, a “young” muscle secretome, neuroprotection, and better cognition later in life….at least for otherwise healthy mice.

Second tests: does this help mice suffering from Alzheimer’s disease-like pathologies?

There are reasons to believe it might. Skeletal muscle alteration is a reported characteristic of AD. Dr. Cortes noted that the disease is associated with lower muscle mass and function in older patients. Higher SM mass has been correlated with higher brain volumes during AD. And higher muscle mass in older patients is associated with a lower risk of developing AD. In mouse models of AD, exercise which caused the release of myokines – those circulating signals from muscle tissues - improve memory, as indicated in this 2019 article:

Lourenco, M.V., Frozza, R.L., de Freitas, G.B. et al. Exercise-linked FNDC5/irisin rescues synaptic plasticity and memory defects in Alzheimer’s models. Nat Med 25, 165–175 (2019). https://doi.org/10.1038/s41591-018-0275-4

Dr. Cortes thinks that her +TFEB mice get the benefits of exercise without the actual exercise because of these circulating signals. To test this, she linked the circulatory systems of different strain of mice, by a surgical technique called parabiosis.

Parabiosis is “the anatomical joining of two individuals, especially artificially in physiological research”.

Her group used mice that are models of AD (PS19 tau mice) and the previously mentioned +TFEB mice. These mice were connected, sharing blood and presumably the myokines, at the ages of 3-6 months, when the AD-like pathology of PS19 mice would normally develop.

• PS19 mice developed the expected symptoms of AD.
• But PS19 mice “parabiosed” – sharing a circulatory system – with +TFEB mice did not. Specifically, they had lower levels of p-tau and fewer “rogue” microglia.

The group is now examining global gene expression, specially, of hippocampus tissue, for these animals.
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Re: Alzheimer's Afternoons Seminar Series Summaries

Postby Fiver » Fri Apr 24, 2020 8:00 am

Alzheimer’s Afternoon Seminar Series
APP and Bioenergetics
Dr. Heather Wilkins, University of Kansas Medical Center
April 23, 2020

Takeaway: The process of degrading old, malfunctioning mitochondria and replacing them with young, healthy mitochondria is important but slows with age (perhaps more in those at risk of AD).

Dr. Wilkins began by reviewing the “Amlyoid Cascade” and the “Phosphorylated Tau” theories of Alzheimer’s disease (AD), noting their similarities. She is, however, most interested in a third theory, called the “Mitochondrial Hypothesis” which posits that mitochondrial dysfunction is the first step in the development of Alzheimer’s Disease. She proposed that mitochondrial dysfunction eventually leads to the aggregation of AB and p-tau. While mitochondrial dysfunction is commonly caused by normal aging, Dr. Wilkins suggested that this occurs more rapidly in those predisposed to AD.

Today she focused on the association between mitochondrial dysfunction and the accumulation of Aβ.

She reviewed the processes by which the amyloid precursor protein (APP) is cleaved to form peptide fragments by the various secretase enzymes to generate Aβ chains of various length (with Aβ 40 and 42 being the most commonly studied). She also reviewed the “timeline of discovery” to note how our understanding of these processes has improved relatively recently.

These resources are available at: http://kualzheimer.org/

Dr. Wilkins explored the evidence that AD is primarily a problem with mitochondrial energy metabolism.

She noted, as support for this view, that AD pathology is associated with increases in mitochondrial DNA (mtDNA) mutations and deletions; a reduction in components of the electron transport chain, including cytochrome C oxidase (Complex IV); decreased glucose uptake and metabolism; and the presence of older, malfunctioning mitochondria.

Her work focuses specifically on the importance of the mitochondrial membrane potential.

A reminder for non-experts: mitochondria, often called the “powerhouse” of the cell produce ATP and other forms of useful stored energy by burning fuels such as sugars and fats.

Mitochondria act much like a battery, separating + and - electrical charges. This separation of charge occurs across the mitochondrial membrane. It separats two compartments - the internal space (the matrix; with a net negative charge) and external space (the intermembrane space, with a net positive charge). The burning (“oxidation”) of fuels provides the power to charge the “mitochondrial battery”. A fully charged mitochondria has an electrical potential of about 0.1 volts. When the two compartments are connected, the flow of protons (positively charged ions) powers the production of ATP.
In general, young mitochondria are superior for producing high amounts of ATP while minimizing the production of toxic byproducts, e.g. reactive oxygen species (ROS).

Dr. Wilkins proposed that the mitochondria membrane potential – specifically those that are too low (hypopolarization) or too high (hyperpolarization) - is linked to the amount of Aβ that accumulates in cells.

To test this, she studies SY5Y neuroblastoma cells, including mutant cell lines that lack key components of the mitochondrial “battery”. She also studies the impacts of drugs which change the polarization of mitochondrial membranes, such as FCCP which causes hypopolarization and oligomycin which causes hyperpolarization.

She observes that:

• Mutant cells lacking key proteins of the electron transport chain have reduced membrane polarization, reduced accumulations of Aβ 40 and 42, and lower beta-secretase levels.
• FCCP acts similarly to cause hypopolarization and reduce Aβ 40 and 42.
• Oligomycin treatments, expected to cause hyperpolarization, led to more Aβ 40 and 42.

In general Dr. Wilkins observes that the mitochondrial membrane potential is positively correlated with the accumulation of Aβ42.
She expanded this work to examine the response of neurons developed from stem cells (iPSCs) of patients confirmed to have had Alzheimer’s disease. The mitochondria of iPSCs from older AD patients did not exhibit altered mitochondrial membrane potentials but, interesting, those from younger patients did.

She then pivoted to discuss a theory called “MAGIC: Mitochondria As Guardians In the Cytoplasm”, described here:

Fang, E.F., Hou, Y., Palikaras, K. et al. Mitophagy inhibits amyloid-β and tau pathology and reverses cognitive deficits in models of Alzheimer’s disease. Nat Neurosci 22, 401–412 (2019). https://doi.org/10.1038/s41593-018-0332-9

This study showed that the recycling of old, poorly functioning mitochondria (“mitophagy”) is inhibited in AD. Those authors conclude: Our findings suggest that impaired removal of defective mitochondria is a pivotal event in AD pathogenesis and that mitophagy represents a potential therapeutic intervention.”

This theory emphasizes the importance of recycling old mitochondria to maintain efficient ATP production, without generating toxic byproducts. This strategy has been proposed to address a range of neurodegenerative disorders, as highlighted by a fund paper we sometimes discuss in class:

Komen JC, Thorburn DR. Turn up the power - pharmacological activation of mitochondrial biogenesis in mouse models. Br J Pharmacol. 2014;171(8):1818–1836. doi:10.1111/bph.12413

Or, if you want to more recent example, try: https://www.mdpi.com/2073-4409/9/1/150/htm#cite

Dr. Wilkins suggested that the APP protein, or parts of it, can clog mitochondrial membrane pores, causing dysfunction. She also noted that beta-secretase is required for the assembly of the mitochondrial electron transport chain.

She noted that mitophagy reduces the accumulation of Aβ 40 and 42, an interesting observation she hopes to explore using her neuronal iPSC system.
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Re: Alzheimer's Afternoons Seminar Series Summaries

Postby Fiver » Thu Apr 30, 2020 8:45 am

Alzheimer’s Afternoon Seminar Series
Dr. Shannon Macauley
April 28, 2020
Targeting vascular KATP channel activity in Alzheimer's disease

Takeaway: Sulfonylurea drugs used to treat diabetes seem to inhibit the accumulation of Aβ by restoring vascular health and calming neuronal activity in the brain, at least in mice.

Dr. Shannon Macauley is an Assistant Professor of Gerontology and Geriatric Medicine at the Wake Forest School of Medicine. She is interested in the connections between two “diseases of aging”, Alzheimer’s disease (AD) and type 2 diabetes.
She uses mouse models to study “how metabolic perturbations, either systemically or within the brain, affect the progression of AD-related pathology, such as the production, clearance, and aggregation of amyloid-beta (Aß) or tau.” Her lab specializes in whole animal physiological experiments using glucose clamps, in vivo microdialysis, biosensors, sleep monitoring and neuroimaging techniques.

Today, Dr. Macauley discussed the importance of hyperglycemia and vascular health in AD.

She began with an introduction to AD and diabetes, using beautiful diagrams to highlight the various brain cell types, and the progression of each disease from preclinical to symptomatic. (The diagrams alone are worth a look at the recorded video of the seminar.)

Next, she asked a seemingly simple question: does hyperglycemia alter Aβ levels in the brain? Her answer was, yes. Using glucose clamps to raise blood sugar levels in mice raised glucose levels of brain interstitial fluid (ISF) and resulted in increased Aβ accumulations. This increase was by ~20% in young mice and ~40% in older mice.

This is consistent with the general view that diabetes can contribute to the progression of AD.

She also noticed increased levels of ISF lactate. She discussed the importance of the lactate shuttle.

A reminder: We often focus on the direct flow of blood glucose to neurons and into glycolysis and the pentose phosphate pathway. However, the lactate shuttle refers to an alternate pathway to fuel neurons. In this case, astrocytes take up blood glucose and do some of the early processing – from sugar to pyruvate and then lactate – before shuttling lactate to neighboring neurons. Lactate can also have a signaling role, providing information to cells.

Previously, lactic acid was considered to be solely a waste byproduct produced when glycolysis outpaced the supply of oxygen. However, more recently we have come to appreciate that most cells produce some lactate, most of the time, even under normal conditions.

Dr. Macauley noticed that brain cell hyperactivity was associated with higher lactate levels which was, in turn, associated with higher levels of Aβ.

She then pivoted to discuss KATP channels, which may explain this.

KATP channels are ATP-sensitive potassium channels. They open or close – depending upon the cellular levels of ATP – to control the amount of positively charged potassium ions (K+) which enter cells.

Thus, they connect cellular energy status to membrane potentials.

They occur in many cell and tissue types and can be manipulated by sulfonylurea drugs. Sulfonylureas are used in the management of Type 2 diabetes. They stimulate insulin release, lowering blood glucose levels.

Here, Dr. Macauley focused on their importance in neurons.

When ATP levels in neurons are high, KATP channels close, preparing nerve cells to fire. This occurs because their membranes become slightly depolarized, making the “trigger” more sensitive. Hence, neurons are more easily excited.
This could, she reasoned, be a link between fuel metabolism and hyper-excitability of neurons.

These channels can be opened or closed artificially using sulfonylurea drugs, commonly used to manage diabetes. Interestingly, these drugs do not pass the blood-brain barrier. In other words, they can not directly alter KATP channels in the brain but might have indirect effects by acting on peripheral tissues.

She asked: would these drugs affect peripheral metabolism in a way that alters KATP channels, the levels of lactate, and Aβ accumulation in the brain?

To assess this, she formulated pellets of glyburide, a sulfonylurea drug, and placed them subcutaneously in mice for slow-release between months 4 and 7. Even though the drug never entered the brain, she found that it reduced Aβ pathology in APP/PS1 mice.

She recorded:
• 50% decrease in Aβ deposition
• A 40% decrease in plaque pathology
• A 30-40% decrease in insoluble Aβ40 and Aβ42
• A 25% decrease in ISF Aβ

How did this occur? Interestingly, she observed no change in the rate of Aβ clearance or degradation, by neurons or microglia. She did, however, find some evidence that the initial production of Aβ was decreased.

She noted that the drug seemed to calm neuronal activity. Specifically, the drug (which did not enter the brain) reduced the amplitude of neuronal activity measured by EEG.

This was another hint that neuron hyperactivity and Aβ pathology are linked.

How is this possible? She hypothesized that this occurred because of a change in blood flow throughout the brain.
To test this, her lab group measured blood flow and oxygen utilization in the brains of mice, using a system of LED lights, lasers, and sensors, to “see” through the intact skull.

They found that glyburide altered the neurovascular response of the brain.

When regions of the brain become active they require extra blood flow and capillaries usually dilate to facilitate this.
However, this response can weaken due to aging or vascular disease, as vessels become stiff.

Here the drug improved vasoreactivity. In short, glyburide seemed to encourage the brain to control blood flow and use oxygen more efficiently. Arterial stiffness was reduced by roughly 50%. The number of KATP channels was increased.

Dr. Macauley summarized that:

• the accumulation of Aβ causes vasoconstriction, lowering blood flow and the availability of oxygen to brain regions and starving them of ATP.
• without adequate ATP the KATP channels are activated, cells membrane are hyperpolarized, neurons become hyperactive and uncoordinated.
• Aβ accumulates further in a cycle.
• drugs such as glyburide seem to break this cycle, even though they do not penetrate the blood-brain barrier.
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Re: Alzheimer's Afternoons Seminar Series Summaries

Postby Fiver » Mon May 04, 2020 8:40 am

Sex differences in metabolic and vascular contributions to dementia. April 30, 2020

Dr. Kristen Zuloaga is an Associate Professor of Neuroscience and Experimental Therapeutics (DNET) at Albany Medical College. A list of her group’s recent publications can be found here:

(Her group has one of the best lab logos too!)

Her seminar focused on sex differences in metabolic and vascular contributions to dementia.

Dr. Zuloaga is interested in several different types of dementia, including classical forms of Alzheimer’s disease and vascular contributions to cognitive impairment and dementia (VCID).

She reminded us that dementias are very often the product of multiple pathologies. About 60-80% of AD patients have vascular pathology. This is called multi-etiology dementia.

By fortunate coincidence, Dr. Zuloaga’s seminar came one day after this article was published:

Montagne, A., Nation, D.A., Sagare, A.P. et al. APOE4 leads to blood–brain barrier dysfunction predicting cognitive decline. Nature (2020). https://doi.org/10.1038/s41586-020-2247-3

So, there is increasing awareness that vascular pathology can be an important contributor to Alzheimer’s disease.

Dr. Zuloaga began by highlighting some basic sex-specific differences:
• The risk of AD is higher for women.
• The risk of VCID is higher for men, at least up to age 90.
• Metabolic disease, especially diabetes at mid-life, is a risk factor for both.

She explained that her lab uses mouse models of AD to study sex differences in risk.

They examine the impact of a high fat (HF) diet which, as she reminded us, has a nutritional content similar to a double cheeseburger and triggers diabetes and hyperlipidemia in these mice. This often results in cognitive decline in mice.
She observes that young female mice fed HF diets do not exhibit these problems. They seem to be protected from the metabolic risks of a poor diet.

Graduate student Abby Salinero asked the question: is this “protection” is lost as female mice age? To test this, she fed female mice of various ages a HF diet (vs a normal control diet; LF) for 3 months. In young 6-week old mice, the females were indeed protected, and less impacted by the poor diet compared to male mice. By early middle-age, however, the female mice had lost this protection; in fact, the female mice exhibited as many or more diet-related metabolic problems than the male mice. Read more about this here:

Salinero, A.E., Anderson, B.M. & Zuloaga, K.L. Sex differences in the metabolic effects of diet-induced obesity vary by age of onset. Int J Obes 42, 1088–1091 (2018). https://doi.org/10.1038/s41366-018-0023-3

And here:

High-Fat Diet-Induced Obesity Causes Sex-Specific Deficits in Adult Hippocampal Neurogenesis in Mice. Lisa S. Robison, Nathan M. Albert, Lauren A. Camargo, Brian M. Anderson, Abigail E. Salinero, David A. Riccio, Charly Abi-Ghanem, Olivia J. Gannon, Kristen L. Zuloaga. eNeuro 23 December 2019, 7 (1) ENEURO.0391-19.2019; DOI: 10.1523/ENEURO.0391-19.2019

Dr. Zuloaga then expanded on this earlier work, by adding one more factor: reductions in brain blood flow that often co-occur with dementia (as in VCID). She presented new data on how these three factors - sex, diet, and cerebral blood flow - interact to impact cognition.

To accomplish this she uses a surgical technique called cerebral hypoperfusion. This reduces blood flow to the right side of the brain by about 15% in mice, mimicking poor blood flow as it might occur with VCID.

Many of these experiments used the common 3xTg AD mouse model, a triple transgenic animal that develops both Aβ and p-tau pathology.

Here she highlighted several sets of experiments by Dr. Lisa Robinson, Olivia Gannon, and Febronia Mansour. Together they examined the interactive impacts of poor blood flow, diet-induced metabolic disease, and sex on:
• Brain blood flow
• Glucose tolerance, and other markers of diabetes
• Body mass, including visceral fat
• Inflammatory markers
• Behavior and cognition

In a series of experiments, they found that:
• Both males and females had the expected reduction in blood flow in temporal cortical region.
• The HF diet led to the expected weight gain; females had highest increase in visceral fat.
• Males exhibited inflammation related to TNFα and IL-6.
• Cognitive impairments were observed in mice subjected to HF diets, reduced cerebral blood flow (to mimic VCID), or the combination of both factors as detected in the:
o Novel object recognition test
o Morris water maze
o Nest building assessment
• Metabolic problems were generally linked to poorer cognitive performance.
• Male and female mice had somewhat different responses, e.g. middle-age females were more effected by the HF diet than middle-age males.
• The accumulation of visceral fat seemed to be especially problematic for females.
• In general, middle-age female mice seemed to display more signs of metabolic problems and cognitive decline, compared to males.

Overall, the studies suggest that sex, poor diet, and reduced blood flow are all important risk factors for AD and related dementias. These risk factors interact, in complex ways, to raise or lower risk.
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Re: Alzheimer's Afternoons Seminar Series Summaries

Postby SusanJ » Mon May 04, 2020 10:12 am

Fiver wrote:Alzheimer’s Afternoon Seminar Series

Thanks again for the summaries.

Dr. Macauley's and Dr. Zuloaga’s research made me think of how we used to call dementia, hardening of the arteries.

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Re: Alzheimer's Afternoons Seminar Series Summaries

Postby Fiver » Tue May 05, 2020 9:58 am

Yep. There seems to to be several things going on with blood vessels - hardening, unresponsiveness, cerebral coronary amyloidosis, leakiness of the blood brain barrier. And apoe4 seems to contribute to most if not all of them. :(
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Re: Alzheimer's Afternoons Seminar Series Summaries

Postby Fiver » Fri May 15, 2020 7:54 am

Dr. Elizabeth Head, Professor, University of California Irvine
Alzheimer’s disease in Down syndrome: Link between Cerebrovascular pathology

On Thursday, May 14, 2020 Dr. Liz Head presented her work on Alzheimer’s disease in Down Syndrome.

Why would it be useful to study the pathology of AD that is associated with Down syndrome?

Down syndrome occurs when an individual has a full or partial extra copy of chromosome 21. This same chromosome carries the gene for the amyloid precursor protein (APP), as well as genes associated with the accumulation of hyper-phosphorylated tau (p-tau) and synaptogenesis. Those with Down syndrome express 1.5 times the usual amount of APP, which translates into increased levels at amyloid beta (Aβ), which becomes apparent at younger ages. Dr. Head cited previous studies which demonstrated that almost all adults with Down Syndrome over the age of 40 have AD pathology, including plaques and tangles. She noted a dramatic spike in pathology between ages 30 and 40 in those with Down Syndrome, even though symptoms of AD dementia may not emerge until decades later.

Her group aimed to test the hypothesis that in those with Down Syndrome the frontal cortex is especially vulnerable to aging and AD. This does seem to be the case. In preserved brain sections they found a loss of connectivity (i.e. white matter integrity) in this region starting by 35 years, sometimes earlier.

This can be caused by cerebrovascular problems, such as atherosclerosis or hypertension which prevent adequate blood flow to the brain. But individuals with Down syndrome rarely have atherosclerosis or hypertension.

Dr. Head’s group wondered about a different type of vascular damage, cerebral amyloid angiopathy (CAA).

Cerebral amyloid angiopathy occurs when amyloid proteins build up on the walls of the arteries, impeding blood flow, disrupting the blood brain barrier, and increasing the risk for dementia.

Indeed, her lab group found evidence of significant CAA – including high levels of Aβ42 and Aβ40 around brain blood vessels in these individuals.

CCA can result in microhemorrhages, or small bleeds in the brain. And Dr. Head found evidence for a greatly increased prevalence of microhemorrhages by staining of archived brain sections and examining non-invasive MRI scans of individuals.

Microhemorrhages can led to physical damage of the brain, as well as inflammation and an activation of immune responses.

This was apparent when gene expression was quantified by RT-PCR in frontal cortex samples. Samples of FC tissue from AD patients showed increases in inflammation – including increased expression of IL-6, TNFα, IL-12, and TFGβ.

Similar tissue samples from individuals with Down syndrome exhibited markers of inflammation even before AD pathology set in.

The combination of DS and AD made the situation worse – not only did these individuals show the highest inflammatory markers but there was also evidence of a chronic immune response as well.

This immune response was clear in microglia observed in the posterior cingulate cortex.

The posterior cingulate cortex (PCC) is buried deep within the brain. It has diverse functions, acting as a sort of connection center in the brain. It is highly active and demands great blood flow than most other areas of the brain.

Microglia are a type of glial cell. They are the primary active immune defense of the central nervous system. Ameboid microglia wander through the central nervous system. Ramified or “resting” microglia are less active but can respond to damage and infection, changing their shape and behavior (becoming “hypertropic” or “dystropic”) to defend brain tissues.

Dr. Head found that normal aging results in fewer ramified or “resting” microglia by more hyper- and dys-tropic cells in both white matter and grey matter of the PCC. This trend was increased in AD and greatly increased in samples from those with both Down syndrome and Alzheimer’s Disease. This lends support to her previous gene expression data.

Together, these results suggest that Aβ accumulations, CCA, and inflammation / immune responses follow a time course and are good targets for intervention.
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Re: Alzheimer's Afternoons Seminar Series Summaries

Postby roxanne » Sun May 17, 2020 12:52 pm

Thank you for your notes Fiver. It probably takes a big chunk of your time. I'm with SusanJ. As a 3/4, I don't see as much success in a Keto Diet as others with 4/4 seem to have. And I struggle and tweak and go on. In any case, these perspectives are very interesting and hopefully something soon will work.

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Re: Alzheimer's Afternoons Seminar Series Summaries

Postby aphorist » Mon May 25, 2020 9:33 am

Thanks for your notes Fiver. I'm referring to them as I review these presentations at 1.75x speed.

Do you (or anyone) have an understanding of why Julia TCW found a ~20% increase in free cholesterol (not cholesterol esters) associated with ApoE4 iPSC but Rik van der Kant indicated that the driver of excess cholesterol (though coincident with pTau) was found in cholesterol esters? Is it that they are different iPSC models?

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Re: Alzheimer's Afternoons Seminar Series Summaries

Postby Fiver » Wed May 27, 2020 9:09 am

Good question. I noticed some differences too. I don't know the specific answer for their studies but overall the researchers are using different models - usually mice, but often different strains - in different ways. The iPSC cells can be different, even different cell types. Sometimes the cells are just one type in isolation, others are grown together with other supporting cell types. Even something like measurement methods or the timing of sample collection could explain it. I generally look for strong trends that show up again and again, in multiple studies.

These seminars somehow remind me how much we are learning and how much we don't know and how complicated it is.

At some point is has to yield a treatment, right?
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