A neurodegenerative disorder characterized by late-onset symptoms like depression, confusion, and memory loss, CTE is caused by repeated impacts to the brain. The disease is most often seen in athletes who play high impact sports and military veterans.

While CTE is known to be associated with abnormal aggregations of the tau protein, which is also observed in diseases like Alzheimer’s disease and traumatic brain injury, no research to date had explored how CTE affected neuron morphology.

In an attempt to get a glimpse into the neurodegenerative mechanisms at work in the CTE brain, researchers at Colorado College quantified the dendritic arborizations of supragranular pyramidal neurons in two regions of the human brain — the frontal and occipital lobes.

Using Neurolucida to reconstruct Golgi-stained neurons from these two regions in 16 human brains (11 cases with CTE and 5 control cases without the disease), a team of researchers led by Dr. Bob Jacobs, observed a general degeneration and greater variability between dendritic systems in CTE brains compared to controls.

Representative Neurolucida tracings of pyramidal neurons in the frontal and occipital lobes from control and chronic traumatic encephalopathy (CTE) groups. CTE tracings show greater variability in dendritic extent compared to control tracings.

According to the study, the dendritic systems of CTE brains showed reductions in seven different measures — dendritic volume, total dendritic length, mean segment length, dendritic segment count, dendritic spine number, and dendritic spine density, as well as dendritic diameter. In contrast to the occipital lobe, dendritic apathy and loss was more severe in the frontal lobe, where p-tau is known to aggregate, possibly acting as a mechanism associated with this pathology, according to the paper.

The researchers also observed a greater variability of morphological differences between dendritic systems in the CTE brains as compared to controls, which were more uniform in size and branching patterns. As outlined in the paper, this variability among neurons in CTE brains might be a result of a combination of the disease’s degenerative effects as well as reorganizational efforts to compensate for the damage.

“This study is the first to document changes in cortical dendritic systems in CTE subjects, which sheds light on an entirely different realm of CTE related neural alterations,” said Dr. Jacobs. “These dendritic changes are probably associated with at least some of the cognitive changes one sees in CTE as well.”

While the authors point out that dendritic degeneration is a normal process in the aging brain, they also explain that their observations of CTE brains in comparison to similarly aged non-CTE brains reveal a possible acceleration in dendritic loss when CTE is present.

Over the course of their study, the scientists traced 640 Golgi-stained neurons with Neurolucida.

“Neurolucida was very effective for this study. The software has come a long way in the last 30 years and has become much easier to use,” said Dr. Jacobs, who, over the course of his career, has traced over 5,000 neurons across 26 different species with the help of Neurolucida.

“I would not have had a research career without the Neurolucida system and the wonderful support of MBF over the years,” he said.

The post Researchers Observe Altered Neuropathology in CTE Brains appeared first on MBF Bioscience.

Some inflammation is normal in a healthy mammalian brain. But as the brain ages, processes can break down, leading to chronic neuroinflammation. This can develop into Alzheimer’s disease, dementia, and other neurodegenerative diseases.

Scientists at Prof. Gerald Muench’s lab, at Western Sydney University say that curcumin, a substance in the spice turmeric, has the potential to lower inflammation in the brain.

In two recent studies, the researchers, led by Dr. Erika Gyengesi, used Stereo Investigator and Neurolucida 360 to reconstruct and quantify glial cells in the brains of mice after feeding them two different curcumin formulations.

“MBF Bioscience’s software helped us immensely to differentiate and follow the changes caused by chronic microglia activation in various areas of the brain during aging, but also to quantify the effects of different modified curcumin products, which otherwise would have been impossible,” said Dr. Gyengesi.

In a study published February, 2020 in Scientific Reports: “Effects of a solid lipid curcumin particle formulation on chronic activation of microglia and astroglia in the GFAP-IL6 mouse model,” (Ullah et al, 2020), the researchers describe positive results after feeding GFAP-IL6 mice — a mouse model of chronic neuroinflammation — 500 ppm of Longvida® Optimised Curcumin (LC) over a course of six months.

Effect of MC on the morphological characteristics of microglial cells in the hippocampus. (A) Morphological assessment of reactive and non-reactive microglia in the hippocampus. (B–H) Microglia in the inflamed mice have significantly larger soma area, soma perimeter and processes compared with the WT mice. High dose MC significantly reduced soma area and soma perimeter compared with GFAP-IL6 mice. However, the same high dose MC significantly increased the number of nodes compared with the GFAP-Il6 mice. It has no effect on the convex area, convex perimeter, dendritic length and number of processes. Significance = *p < 0.05, **p < 0.001, ***p < 0.0001, ****p < 0.0001.

Stereological analysis of the mouse brains revealed lower levels of activated microglia in the hippocampus (26 percent less) and in the cerebellum (48 percent less) in GFAP-IL6 mice that were fed the curcumin diet, compared to GFAP-IL6 mice fed a normal diet. They also quantified astrocytes — another cell type activated in response to neuroinflammation, finding decreased levels in the hippocampus (30 percent less). TSPO+ cells — another marker of brain inflammation, decreased as well (by 24 percent in the hippocampus and 31 percent in the cerebellum) in the experimental mice compared to controls.

Dr. Gyengesi and her team then checked to see what effect the curcumin formulation had on cell morphology. Using Neurolucida 360 they reconstructed 16 to 20 astrocytes in the hippocampus of each brain of the four different cohorts (wild type normal-fed, wild type LC-fed, GFAP-IL6 normal-fed, GFAP-IL6 LC fed).

They found that in GFAP-IL6 mice, LC decreased “dendritic length of microglia and the convex area, convex perimeter, dendritic length, nodes and number of processes of astrocytes in the hippocampus.” The curcumin formulation also decreased the unusually enlarged soma area and perimeter of neurons in the cerebellum. Increased pre- and postsynaptic protein levels and improved balance were observed as well in LC-fed GFAP-IL6 mice.

In another study, published by the group earlier this year, in the journal Frontiers in Neuroscience, “Evaluation of Phytosomal Curcumin as an Anti-inflammatory Agent for Chronic Glial Activation in the GFAP-IL6 Mouse Model” (Ullah et al, 2020), the researchers tested a different curcumin formulation. This time, they fed GFAP-IL6 mice a soy-lecithin based phytosomal curcumin formulation (Meriva® curcumin).

After feeding the GFAP-IL6 mice three doses of Meriva curcumin over a period of just four weeks, they saw promising results. They quantified lower numbers of activated microglia in the hippocampus (26.2 percent less) and in the cerebellum (48 percent less) compared to those in the population of GFAP-IL6 mice, which was fed a normal diet. Lower levels of GFAP+ astrocytes were also observed in this group.

As in the previous study, the scientists witnessed morphological differences in the mice fed the curcumin diet, including a decrease in the size of the already enlarged soma.

“Using Neurolucida and Stereo Investigator, we have demonstrated that various curcumin formulations with increased bioavailablity have the capability to attenuate chronic inflammatory pathology, by not only reducing activated glial numbers but also reversing their activated morphological state,” said Dr. Gyengesi.

Citations:

Ullah F, Asgarov R, Venigalla M, Liang H, Niedermayer G, Münch G, Gyengesi E. Effects of a solid lipid curcumin particle formulation on chronic activation of microglia and astroglia in the GFAP-IL6 mouse model. Sci Rep. 2020;10(1):2365. Published 2020 Feb 11. doi:10.1038/s41598-020-58838-2 https://pubmed.ncbi.nlm.nih.gov/32047191/

Ullah F, Liang H, Niedermayer G, Münch G, Gyengesi E. Evaluation of Phytosomal Curcumin as an Anti-inflammatory Agent for Chronic Glial Activation in the GFAP-IL6 Mouse Model. Front Neurosci. 2020;14:170. Published 2020 Mar 12. doi:10.3389/fnins.2020.00170 https://pubmed.ncbi.nlm.nih.gov/32226360/

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Amyloid plaques and tau tangles are the hallmarks of Alzheimer’s disease (AD) pathology, but synapse loss is what causes cognitive decline, scientists say. In a paper published in Science Signaling, researchers at the Herskowitz Lab, at the University of Alabama at Birmingham, used Neurolucida 360 to analyze spine density and dendritic length in hAPP mice — a mouse model of AD. Their findings describe a treatment that could protect against synapse loss and prevent the onset of dementia in patients at risk for Alzheimer’s disease.

Targeting LIMK1 to Protect Against Dendritic Damage

In their study, the scientists targeted LIMK1, an enzyme that regulates the size and density of dendritic spines. Previous studies have shown that in animal models of AD, LIMK1 activity is increased, causing synaptic hyperactivity and dendritic damage. After confirming this phenomenon, the research team set out to find a way to inhibit LIMK1, which lies downstream of two other important players in dementia pathology — the Rho-associated kinases known as ROCK1 and ROCK2.

Representative maximum-intensity high-resolution confocal microscope images of dye-filled dendrites, from CA1 hippocampal neurons in mice, after deconvolution and corresponding 3D digital reconstruction models of dendrites. Scale bar, 5 μm. Colors in digital reconstructions correspond to dendritic protrusion classes: blue, thin spines; orange, stubby spines; green, mushroom spines; and yellow, dendritic filopodia.

Previous studies have shown that severe side effects including fatally low blood pressure are associated with the inhibition of ROCK1 and ROCK2, so the researchers looked further down the signaling pathway to the LIMK1 point, potentially discovering a truly valid target in the fight to prevent dementia onset.

Since LIMK1 has also been a target in cancer treatment, the researchers turned to SR7826, an experimental drug currently in development to treat cancer patients. They found that administering SR7826 suppressed LIMK1 activity and protected dendritic morphology against the damage commonly seen in a brain afflicted with dementia. By reconstructing the mouse neurons with Neurolucida 360, they observed increased dendritic spine length and density in the experimental group, compared to controls.

Using Neurolucida 360 to Analyze Dendritic Spine Morphology

Herskowitz and his team have used Neurolucida 360 in previous studies, and used the software extensively throughout the current study to image and quantify dendritic morphology.

“Neurolucida 360 is a remarkable system that has provided us with tools to study dendritic architecture in cultured neurons, rodent models, and humans, with outstanding precision and detail,” said principal investigator Jeremy Herskowitz, Ph.D.

Their first step was to confirm that increased ROCK1 or ROCK2 activity caused detrimental structural effects on dendritic spines. To do this, they analyzed rat hippocampal neurons that had been transfected with either green fluorescent protein (GFP), an actin-binding peptide, ROCK1, or ROCK2. Controls were transfected with empty vectors.

Using Neurolucida 360, they digitally generated neuron reconstructions and quantified dendritic spine length and density in all of the experimental groups. Neurons expressing ROCK1 showed significantly reduced spine length compared to vector or GFP controls, while neurons expressing ROCK2 showed significantly reduced spine density.

They then used Neurolucida 360 to determine that two different mechanisms dictate the distinct impacts ROCK1 and ROCK2 have on dendritic structure — ROCK1 kinase activity regulates spine length through myosin-actin pathways, whereas ROCK2 kinase activity controls spine density through LIMK1-cofilin-actin signaling.

Further experiments used Neurolucida 360 to analyze dendrites of neurons injected with both amyloid-β oligomers and a virus expressing ROCK1- or ROCK2-targeted RNA. This allowed the scientists to discern that ROCK2, and not ROCK1, works with Aß oligomers to induce spine degeneration.

“Treatment of hAPP mice with a LIMK1 inhibitor rescued Aβ-induced hippocampal spine loss and morphologic aberrations. Our data suggest that therapeutically targeting LIMK1 may provide dendritic spine resilience to Aβ and therefore may benefit cognitively normal patients that are at high risk for developing dementia. (2019, Henderson et al)

Henderson, BW., Greathouse, KM., Ramdas, R., Walker, CK., Rao, TC., Bach, SV., Curtis, KA., Day, JJ., Mattheyses, AL., Herskowitz, JH. 2019. Pharmacologic inhibition of LIMK1 provides dendritic spine resilience against β-amyloid. Science Signaling Vol. 12, Issue 587 DOI: 10.1126/scisignal.aaw9318 (https://stke.sciencemag.org/content/12/587/eaaw9318)

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Astrocytes (GFAP) in the dentate gyrus of a mouse hippocampus. Image courtesy of Dr. Ahmad Salehi, Stanford University.

It is well known that physical exercise eases the symptoms of neurodegenerative disorders like Alzheimer’s disease and helps to prevent their onset. Researchers at Stanford University are working on figuring out how it happens.

In their study, published in the journal Brain Structure and Function, scientists in Dr. Ahmad Salehi’s lab examined the effects of physical exercise on astrocytes in a region of the mouse brain that is critical for cognition – the dentate gyrus of the hippocampus. Previous studies have shown that an increase in the expression of brain-derived neurotrophic factor (Bdnf) occurs in this region after exercise (Philips, Salehi et al 2014). Bdnf is a protein that supports the survival of existing neurons and encourages new growth, playing an important role in cognitive function.

While the current study reconfirms that exercise generates increased levels of Bdnf (more than a fourfold increase in exercised mice versus non-exercised mice), it also describes several new findings including increased synaptic load in the dentate gyrus, alterations in the morphology of astrocytes, and changes in the orientation of astrocytic projections toward dentate granule cells.

The authors speculate that the changes they observed may be attributed to increased expression of a receptor called TrkB, which astrocytes express in response to increases in Bdnf levels. According to the paper, TrkB binds to Bdnf, activating the mechanisms behind neuronal development.

“Our study suggests that astrocytes actively respond and could indeed mediate the positive effects of physical exercise on the central nervous system and potentially counter degenerative processes during aging and neurodegenerative disorders,” (Fahimi, et al 2016).

The researchers used Neurolucida to determine the location, the extent, and orientation of astrocytic projections, finding a significant increase in the length of astrocytic projections in exercised mice.

“Neurolucida is one of the very few systems that combines complex morphometrical quantification with beautiful display of the results,” said Dr. Salehi, Clinical Professor, Department of Psychiatry and Behavioral Sciences at Stanford Medical School.

Since astrocytes help prevent excitotoxicity in the brain by removing excess glutamate from extracellular space, the researchers speculate that the increased length of astrocytic projections they observed in exercised mice could make this process more efficient.

Differences in the orientation of astrocytic projections were also reported, with the majority of projections of exercised mice directed toward the dentate granule cell layer – a region featuring increased levels of Bdnf release and synthesis after exercise.

The number of astrocytes in the molecular layer of the dentate gyrus in exercised and non-exercised mice was quantified with Stereo Investigator, however, there was no significant difference in astrocyte populations between the two groups.

“In summary, our study suggests that astrocytes constitute an important element in mediating the positive effects of physical exercise in the dentate gyrus of the hippocampus. Furthermore, it appears that physical exercise-induced release of Bdnf by the DG leads to a significant alteration in structure and function of astrocytes in protection against glutamate toxicity during aging and a number of neurodegenerative disorders,” (Fahimi et al 2016)

Fahimi, A., Baktir, M.A., Moghadam, S., Mojabi, F.S., Sumanth, K., McNerney, M.W., Ponnusamy, R., Salehi, A. Brain Struct Funct (2016). doi:10.1007/s00429-016-1308-8

Phillips, C., Baktir, M.A., Srivatsam, M., Salehi, A. Front. Cell. Neurosci., (2014) https://doi.org/10.3389/fncel.2014.00170

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Micrograph of cholinergic neurons in the nucleus basalis of Meynert. Image from Wikipedia.

Cholinergic neurons degenerate at devastating rates in Alzheimer’s disease, but Dr. Mark Tuszynski and his team at the University of California, San Diego may have found a way to slow the decline.

Their study, published in JAMA Neurology, reports that nerve growth factor gene therapy increased the size, axonal sprouting, and signaling of cholinergic neurons in 10 Alzheimer’s disease patients.

The patients were enrolled in a clinical trial between 2001 and 2012. Ex vivo and in vivo methods of gene therapy were used to deliver nerve growth factor – a protein that protects neurons and stimulates growth – to the patients. Eight received an implant of their own skin cells that were genetically modified to express nerve growth factor (ex vivo ) and two patients received injections that induced neurons already in the brain to express nerve growth factor (in vivo). In all 10 patients, gene therapy was delivered to the nucleus basalis of Meynert – part of the basal forebrain rich in cholinergic neurons that undergoes degeneration during Alzheimer’s disease. 

The patients’ survival time ranged from one to 10 years. After they had died, researchers analyzed the effects of nerve growth factor on cholinergic neurons.

The axons of cholinergic neurons, labeled with p75, grew toward the source of the nerve growth factor in all 10 patients. To determine if there was a change in cell size, researchers used the nucleator probe in Stereo Investigator to analyze cholinergic neurons of 3 patients who received gene therapy via the ex vivo method in one hemisphere – the other hemisphere was used as a control. Results from Stereo Investigator showed that cell bodies were larger in the treated hemisphere vs. the untreated hemisphere.

Finally, to find out if nerve growth factor induced signaling within cells, the researchers analyzed the amount of CREB and c-fos – markers for cell activation – in 2 patients who received nerve growth factor in vivo. An elevated amount of CREB and c-fos was found when compared to control regions. Neurons exhibiting tau pathology also expressed nerve growth factor, indicating that degenerating cells could respond to nerve growth factor gene therapy.

A phase 2 clinical study is currently under way to report cognitive outcomes in patients with Alzheimer’s disease.

“Collectively, these anatomical findings support the rationale for clinical trials to test the hypothesis that sustained growth factor delivery over time can reduce cell degeneration and stimulate cell function in chronic neurodegenerative disorders, thereby slowing functional decline,” Tuszynski, et al.

Tuszynski, M.H., Yang, J.H., Pay, M.M., Masliah, E., Barba, D., U, H.S., Conner, J.M., Kobalka, P., Roy, S., and Nagahara A.H. (2015). Nerve Growth Factor Gene Therapy: Activation of Neuronal Responses in Alzheimer Disease. JAMA Neurology, published online August 24, 2015. DOI: 10.1001/jamaneurol.2015.1807.

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The study, published in the Journal of Comparative Neurology, provides evidence of Alzheimer’s disease precursors in the western lowland gorilla. Their findings broaden the scientific community’s understanding of the aging brain of some our closest living relatives and offer new insights for Alzheimer’s disease research.

“As great apes and humans share numerous anatomical and physiological similarities due to their close genetic ancestry, the knowledge of interspecies differences in AD-like pathology could provide clues to the mechanisms underlying AD pathology in humans,” the authors say in their paper.

Cortical neurons containing tau, termed neurofibrillary tangle, seen in the human brain with Alzheimer’s disease. The researchers used Neurolucida to chart similar lesions in the gorilla brain.

The researchers studied neocortical and hippocampal specimens from western lowland gorillas provided by the Great Ape Aging Project, an organization dedicated to the advancement of knowledge about great apes. Formerly housed at zoos and aquariums around the United States, the gorillas all died of natural causes at ages ranging from 13 to 55-years-old.

Their qualitative analyses of immunohistochemically stained sections of the apes’ frontal cortices and hippocampi revealed an age-related increase in Aβ plaques and Aβ-positive blood vessels, with “many more” APP/Aβ-positive plaques in the cortex of the oldest gorilla – the 55-year-old female, compared with the 50-year-old female. They also saw higher levels of Aβ plaques in the neocortex and hippocampus of females, while male gorillas had more Aβ-positive blood vessels. Also interesting were the differences at varying cortical levels. The researchers saw compact, strongly labeled plaques in the subgranular layers (I-III) and paler, larger plaques in the infragranular layers (V-VI), according to the paper.

Then, the researchers used Neurolucida to map APP/Aβ-immunoreactive plaques and Alz50-immunoreactive neurons in the neocortex and hippocampus of the 55-year-old female. Alz50 is a stain for a phosphorylated epitope of tau protein. Tau is the main component of neurofibrillary tangles.

“Neurolucida allowed us to chart labeled images in a timely and efficient manner,” Dr. Elliot Mufson, a lead author of the study said.

In summary, this research paper reports the first evidence of age-related Aβ plaques in gorillas, and the first evidence of tau-positive profiles in gorillas. These findings show that gorillas are relevant in the study of Alzheimer’s disease.

Perez, S. E., Raghanti, M. A., Hof, P. R., Kramer, L., Ikonomovic, M. D., Lacor, P. N., Erwin, J.M., Sherwood, C.C., Mufson, E. J. (2013). Alzheimer’s disease pathology in the neocortex and hippocampus of the western lowland gorilla (Gorilla gorilla gorilla). Journal of Comparative Neurology, doi: 10.1002/cne.23428

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Rather than focusing on conventional methods of neurotrophic factor delivery, which have always been extremely difficult and resulted in undesirable side effects, the Ceregene researchers took a different approach. They turned to gene therapy. Instead of delivering the restorative protein to the targeted sites in the brain, the Ceregene researchers developed a way to deliver only the gene for the protein. Once in place, the gene induces local cells to make the protein on site.

“[CERE-120] is designed to deliver the gene for NRTN to targeted neurons, and subsequently program these neurons to provide continuous, long-term, predictable NRTN expression in selective, stereotactically-targeted regions of the brain,” say the authors in their paper published in the Neurobiology of Aging.

During ten years of testing, which initially involved rats and monkeys, before working with 80 human patients with Parkinson’s Disease, the researchers performed exhaustive experiments on the therapy’s safety and efficacy. In the paper, the authors describe how they achieved their main goal of NRTN expression throughout the targeted region, while avoiding exposure to other areas of the central nervous system, and inducing positive responses in the brain.

To measure the effectiveness of the therapy, the researchers evaluated patients one year after surgery and tested a series of “motor-related” and “quality-of-life” end points commonly used in Parkinson’s Disease therapy testing. Nineteen of the twenty-four end points favored CERE-120 compared with the sham control group.

“These data provide the first ever, properly controlled, “proof-of-concept” evidence that neurotrophic factors can improve the clinical status of an age-related neurodegenerative disease,” the authors say.

Neurolucida played an important role in the research. To determine proper dosage, the researchers created a 3D model of the brain with Neurolucida, MRI images, and histological slides. The 3D computer model helped the scientists visualize the target brain region so they could determine how much of the NRTN gene should be administered and where exactly it should be directed to “provide the greatest coverage, with the fewest needle tracts, while avoiding protein expression outside its boundaries,” according to the paper.

“The collective characteristics of safe, very long-term, controlled protein expression that can be targeted to specific sites or systems supports the idea that gene transfer may have finally solved the delivery problems required for neurotrophic factors,” conclude the authors.

Read the full paper “Advancing neurotrophic factors as treatments for age-related neurodegenerative diseases: developing and demonstrating ‘clinical proof-of-concept’ for AAV-neurturin (CERE-120) in Parkinson’s disease” on Ceregene’s website.

Bartus, R. T., Baumann, T. L., Brown, L., Kruegel, B. R., Ostrove, J. M., & Herzog, C. D. (2012). Advancing neurotrophic factors as treatments for age-related neurodegenerative diseases: developing and demonstrating “clinical proof-of-concept” for AAV-neurturin (CERE-120) in Parkinson’s disease. Neurobiology of Aging, 34:35-61

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Alzheimer’s disease is the most common form of dementia. Most cases occur in people over 65, and are not genetically inherited. Roughly five percent of Alzheimer’s patients suffer from familial Alzheimer’s disease (FAD), an uncommon form that tends to strike sooner, and is related to a genetic predisposition – most commonly, a mutation in the presenilin 1 gene (PS1).

A recent study, led by Dr. Miguel A. Gama Sosa of the Mount Sinai School of Medicine in New York, shows that the mutated PS1 gene contributes to the vascular pathology of familial Alzheimer’s disease.

During the course of their research, Dr. Gama Sosa’s team used Stereo Investigator for the stereologic analyses of transgenic mouse brains.

“We quantified the density, area and length of the vasculature in the hippocampus of mice that express a mutation associated with familial Alzheimer’s disease,” explained coauthor Dr. Gregory A. Elder of the James J. Peters Veterans Affairs Medical Center in the Bronx.

“We found [Stereo Investigator] easy to use and adaptable to the requirements of the study,” he added.

Read “Age-Related Vascular Pathology in Transgenic Mice Expressing Presenilin 1-Associated Familial Alzheimer’s Disease Mutations” at the American Journal of Pathology.

{Image: Anti collagen IV-peroxidase staining of the hippocampal vasculature of a 26 month-old transgenic mouse expressing a human presenilin 1 (PSEN1) transgene harboring the M146V mutation associated with familial Alzheimer’s disease (FAD). Present are vascular abnormalities including string, tortuous and double-barreled vessels.  In addition many vessels are irregular with decreased diameters. – Courtesy of Miguel Gama-Sosa Ph.D.}

Miguel A. Gama Sosa, Rita De Gasperi, Anne B. Rocher, Athena Ching-Jung Wang,  William G.M. Janssen, Tony Flores, Gissel M. Perez, James Schmeidler, Dara L. Dickstein, Patrick R. Hof, and Gregory A. Elder (2010), “Age-Related Vascular Pathology in Transgenic Mice Expressing Presenilin 1-Associated Familial Alzheimer’s Disease Mutations.” American Journal of Pathology, 176:353-368

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