Scientists Isolate Toxic Key to Alzheimer's Disease

NIA NEWS
For Immediate Release: June 23, 2008

Scientists Isolate Toxic Key to Alzheimer's Disease
Soluble Beta-Amyloid Protein Fragments May Damage Brain Cells, Study Finds

Scientists have long questioned whether the abundant amounts of amyloid plaques found in the brains of patients with Alzheimer's actually caused the neurological disease or were a by-product of its progress. Now, using new research techniques, scientists have shown that a two-molecule aggregate (or dimer) of beta-amyloid protein fragments may play a role in initiating the disease.

The study, supported by the National Institutes of Health, suggests a possible new target for developing drug therapies to combat the irreversible and progressive disorder.

Ganesh M. Shankar, Ph.D., and Dennis J. Selkoe, M.D., of Brigham and Women's Hospital and Harvard Medical School, conducted the study in collaboration with other researchers at Harvard and in Ireland at University College Dublin, Beaumont Hospital and Royal College of Surgeons Ireland, and Trinity College Dublin. The National Institute on Aging (NIA), part of NIH, funded the study which appears online in the June 22, 2008, Nature Medicine.

Alzheimer's disease is marked by the build-up of plaques consisting of beta-amyloid protein fragments, as well as abnormal tangles of tau protein found inside certain brain cells. Early in the disease, Alzheimer's pathology is first observed in the hippocampus, the part of the brain important to memory, and gradually spreads to the cerebral cortex, the outer layer of the brain.

In this study, researchers tested cerebral cortex extracts from brains donated for autopsy by people aged 65 and older with Alzheimer's and other dementias, as well as those without dementia. The extracts contained soluble one-molecule (monomer), two-molecule (dimer), three-molecule (trimer) or larger aggregates of beta-amyloid, as well as insoluble plaque cores. The researchers then injected the extracts into normal rats or added the extracts to slices of normal mouse hippocampus.

Shankar, Selkoe and colleagues discovered that both the soluble monomers and the insoluble plaque cores had no detectable effect on the hippocampal slices. However, the soluble dimers induced certain key characteristics of Alzheimer's in the rats. The dimers impaired memory function, specifically the memories of newly learned behaviors. In the mouse hippocampal slices, the dimers also reduced by 47 percent the density of the dendrite spines that receive messages sent by other brain cells. The dimers seemed to be directly acting on synapses, the connections between neurons that are essential for communication between them.

To confirm this effect, the researchers then injected certain antibodies against beta-amyloid protein fragments. These latched onto and inactivated the dimers, preventing their toxic effects in the animal models. However, much work remains to be done before inactivation of dimers could move into the clinic.

"Scientists have theorized for many years that soluble beta-amyloid may be critical to the development and progression of this devastating disease. Now these researchers have isolated a candidate causative agent from brains of people with typical Alzheimer's and directly tested it in an animal model," said NIA Director Richard J. Hodes, M.D. "While more research is needed to replicate and extend these findings, this study has put yet one more piece into place in the puzzle that is Alzheimer's."

The animal findings were consistent with what the researchers found when they examined the brain tissues of people who had been clinically diagnosed with Alzheimer's and those without dementia. They detected soluble dimers and some trimers of amyloid in the brains of patients with Alzheimer's, but none or very low levels in those free of the disorder. Some people free of the disorder, however, did have insoluble amyloid plaques in their brains.

"These findings may help explain why people with normal cognitive function are sometimes found to have large amounts of amyloid plaques in their brains, which has been a puzzle for some time," said Marcelle Morrison-Bogorad, Ph.D., director of the NIA Division of Neuroscience.

"Their findings noted that the brain of an individual who was never clinically diagnosed with dementia was found with abundant insoluble Alzheimer's plaques, but no soluble beta-amyloid."
Selkoe and Shankar noted that further insights into the early stages of this disease process may answer questions not only about Alzheimer's, but also about age-related memory impairments.

"The approaches we used to isolate dimers and the widespread availability of tissues from brain banks, open new avenues of investigation into how these aggregates induce Alzheimer's disease," said Selkoe. "We still need to find out why dimers in particular are so destructive to neurons."
NIA leads the federal government effort conducting and supporting research on the biomedical and social and behavioral aspects of aging and the problems of older people.

For more information on aging-related research and the NIA, please visit www.nia.nih.gov. The NIA provides information on age-related cognitive change and neurodegenerative disease specifically at its Alzheimer's Disease Education and Referral (ADEAR) Center site at www.nia.nih.gov/Alzheimers. To sign up for e-mail alerts about new findings or publications, please visit either Web site.

The NIH -- The Nation's Medical Research Agency -- includes 27 Institutes and Centers and is a component of the U.S. Department of Health and Human Services. It is the primary federal agency for conducting and supporting basic, clinical and translational medical research, and it investigates the causes, treatments and cures for both common and rare diseases. For more information about NIH and its programs, visit www.nih.gov.

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What you should know about Alzheimer's

http://health.nytimes.com/health/guides/disease/alzheimers-disease/overview.html?WT.mc_id=HL-D-I-NYT-MOD-FP-CM2-HL-0308-ALZ&WT.mc_ev=click&mkt=HL-D-I-NYT-MOD-FP-CM2-HL-0308-ALZ

I won't go into great detail, just say that if you suspect that you or someone you love has this dread disease, don't put off doing something about it. This primer from the health editors at the New York Times gives warning signs, discusses treatment options, medical tests (that at least two doctors told me did not exist) and some very practical suggestions for dealing with it. From experience, I know that this is good information and well worth your time if you are worried or even just curious. Wish I had had this about four years ago.

Shared Memories

The first friend to share a story about Frances was Elaine H.

My favorite memory of your mother was the day I was invited for lunch to share my reunion story with you and her. We had homemade biscuits and vegetable soup and she was so joyous that day. We laughed and cried together as we ate a marvelous lunch at the dining room table. That day she was like a mother to me and continued to be a great friend who I always enjoyed being around. What a great cook and baker she was! There was always a twinkle in her eye and a wit that one never knew when it was coming. One great lady was Miss Frances........

Exhaling slowly

It's been just over a month since I lost Mom. While things will never be the same again, life is beginning to return to normal.

Friends sent some really lovely cards and thoughtful email messages. Reading them helped. I am sad that my email program (Outlook Express) dumped about 3000 recent messages including all of those lovely condolence letters before I had time to print them out. My intention was to save them so I am disappointed that my computer swallowed them but I remember how they made me feel and that was what mattered. (I really hope that it did not delete any that I had not yet had time to read!)

I also received a really upsetting note from someone I would have defined as a cordial acquaintance, though not a friend, before this item arrived in the mail. Allow me to explain how this happened.

I began writing notes to thank people for flowers, gifts of food, etc. a couple weeks ago. I think it's fair to say that I was thinking on paper as I wrote. Friends who know that I cared for Mom 24/7 for 15 months understand that did not allow me to work away from home and that money was always tight. I did freelance, still do and that kept us in grocery money and paid for other necessities but it didn't pay for everything. So I used Mom's savings and mine to keep her in this house rather than move her into a nursing home. I understand that changes like that can really send someone with Alzheimer's into the abyss. And I was glad that I was able to do that but, toward the end, I was worried about how I would be able to continue when I had no more savings to dip into. When I wrote in several of my acknowledgements that I was "broke until I found a job" it was an expression of relief because now I can seek additional work. In that context, it never occurred to me that anyone who knew Mom and me would twist that statement into a request for a handout.

I am also free to work away from home now. And I'm looking for work opportunities. My household income has been reduced by the loss of Mom's pension but so have the bills for medicine, that increased exponentially when she fell into the Medicare Rx "donut" hole, and other items necessary to Mom's care. My concerns about finances were exacerbated for months by the fact that I could not leave Mom alone to go out to work. Now I can. One of my first orders of business was to let people know I am looking for work, hence my comment. And I have gotten some employment leads and client referrals as a result!

But when I first read it, I was really nonplussed. I guess I can see how someone might misinterpret my words, especially someone who is not particularly close to me and has not kept in touch during Mom's long decline. But wouldn't the most appropriate thing to do assuming she really did interpret this as a request for money be to ignore it? Instead, I got this really hurtful letter. One friend who read the "nasty gram" cautioned me to keep in mind that the interpretation only proved that, although I was the one grieving, the writer thought it was "all about her."

But the law of unintended consequences kicked in. Although I had wept often in the days leading up to Mom's death, I had been unable to cry since. Even at the memorial service I only shed a few tears -- for which I was grateful since I hate to lose my composure in public. But that spiteful note did the trick. I cried for the rest of the day and most of the night remembering all I had lost and also the grievances I had been hanging on to regarding people and things whom I felt had used Mom ill over the years. The next afternoon I realized that I was no longer numb so there was hope that I could begin to work through this loss because I could cry for Mom and for myself. And I realized something else.

Over a year ago, I was in a difficult place emotionally. My circumstances left me feeling beat down by life. And there were a few individuals who had exacerbated that feeling by kicking me when I was down. Life is like that. And most "blows" don't bother us when we are going strong but take a tremendous toll when we are not. A friend sent me an article about how hanging on to resentment robs one of energy. Realizing that I could not afford to spend the limited energy that I had on resenting people who had added to my burdens or declined to lighten them when they had the power. So I decided I had to forgive and forget and get past those injuries. I did. And I felt better. I landed a couple of freelance clients, which really helped me through that 15-month incarceration. But that letter reminded me that there were some resentments that I had only buried, particularly with regard to persons who had added to Mom's burdens because the writer was one of them. I had put that out of my mind but, the letter brought those memories of how hurt Mom was rushing back. And I knew that I could not carry that weight around with me.

I made up my mind to forgive the injury. I confess that I found it harder to forgive someone who hurt Mom but I am working my way toward it, ever mindful of the fact that doing so releases ME from the prison of my resentment and allows the positive energy to flow. I've come a long way already but still have a ways to go.

Rebooting

The past week is almost a blur. I have been trying to repair my sleep deficit. I haven't even begun to answer cards and flowers but people were very kind.

One of the things that I enjoyed after the service was stories about Mom that people shared with me so I would like to ask you to send me remembrances of Mom and, if you don't mind, I will post them.

Thanks!

Exhaustion

I am so tired right now that I can hardly function. The telephone started at shortly after 9 a.m. and has punctuated the day. I was glad to hear from everyone who called but not able to function as well as I will when I have had some rest. I napped between calls until about 11:30 when I decided I was more hungry than sleepy. Friends who have brought by already prepared food and snacks are a real Godsend. I don't feel like cooking.

We are making plans for the service. I think it will be very nice and that she would approve. Rather than gloom and doom, we are going for something with a positive message. And I have to note that thinking about the service has been good comfort "therapy" yesterday and today. It doesn't take my full faculties to leaf through the hymnbook and think about music she would like or that might be comforting to those of us who are left. I spent part of yesterday selecting scriptural passages that I thought fitting. I choose to include one that my father helped me to memorize years ago because it became special to us. I recited it at a church service that recognized the study and work of members of the Girls Auxiliary of the Woman's Missionary Union, Mom was GA director at the time. It's a long passage and it took me some time to master it. After that, whenever we heard it, it was like a private signal between us reminding us of that time in our life before we lost my dad.

Bill used to be my "next door neighbor" at school. His office was next to mine as I was one of those invasive members of the communication arts department who were sprinkled throughout Fulton Hall in the midst of other departmental offices. I was surrounded by the music department of which he is a faculty member. He's arranging the music for the service so I know it will be lovely. My neighbor, Ruth, who works for the school board is reading a poem by John Donne and another former neighbor, who still works at the church office on the other side of me is going to read that special passage of scripture. There's no one left but me who would fully understand the significance of that passage to our family, so that's something that is just for me.

Two of my former students, and close personal friends, are preparing Mom's Eulogy. I am thrilled. I know that it will be lovely and that it will strike just the right note. One of them was her regular Tuesday night sitter when I was still teaching and they became very fond of one another. The other student is possibly a distant relative of Mom (but we claim her regardless) and on a couple of occasions when she spent time with Mom, she got to hear tales of Mom's life as a child that including living on Assateague Island, very near when this student now lives at Chincoteague. Mom went to school to hear their research presentation at the Undergraduate Research Conference and thought that they were very special, which they are.

I've had condolences from folks who knew Mom and others who only know me but know about the role she played in my life. Those have meant a great deal to me. The ones that came via email I will have to print out and save. Some of them are just lovely. Knowing what her life and personality meant to others is a great comfort.

Mom has been wanting to "go home" for months, and now she has. I'm more tired than anything else right now. I have grieved for the past week because I knew it was coming. Now we can both rest.

Pennagal



Obituary

Frances ---------, 86, died yesterday at her home in Salisbury from complications of Alzheimer’s.

------------- was born near Snow Hill in 1921 and was the daughter of Samuel --------- and Daisey ----------. Her husband Vaughn --------- died in 1971.

Surviving are her daughter, Ann ------, a nephew, Edward -------., both of Salisbury, and honorary daughter, Mary -------- of Williamstown, PA. She also leaves a brother, Samuel -----------, of Salisbury, and a nephew, Kenneth ------- of Brick, NJ, six grandnieces and three grandnephews and two great-grandnieces and several cousins. Her brother, Edward --------, and her nephew, Samuel -------, preceded her in death.

When she was active, she volunteered many hours to church and charity work. For several years, she co-wrote a cooking column with her daughter in Rural Living Magazine. She made a home for both her parents in their final years. Many Salisbury residents will remember waving to her while she worked in her Newtown garden.

A celebration of her life will be held on Saturday, May 24 at ---------- in Salisbury at 3 p.m. Friends may call an hour before the service.