New Culprit in Alzheimer’s Disease Development Identified

Findings may influence strategies for treatment.

A recent study conducted at Nathan S. Kline Institute for Psychiatric Research (NKI) and NYU Langone Medical Center implicates a new culprit in Alzheimer’s disease development. The research reveals that ßCTF — the precursor of the amyloid beta (Aß) peptide — acts at the earliest stage of Alzheimer’s to initiate a range of abnormalities leading to the loss of groups of neurons critical for memory formation. Results from the study are published online July 21, 2015 in the journal, Molecular Psychiatry, and the article has been selected for an issue cover.

The recent study findings involving ßCTF have significant implications for treatment strategies and furthering the course of Alzheimer’s drug development. Presently, the most common strategy for treating Alzheimer’s disease is targeting the amyloid ß peptide, which has had modest success in clinical trials. Findings from this research suggest that drugs that may reduce βCTF levels as well as beta-amyloid, such as the class of BACE1 inhibitors currently under development, may help slow or stop the progression of Alzheimer’s disease.

βCTF is formed during endocytosis, the process by which cells absorb nutrients and sample various materials from the outside environment. It has been known for some time that abnormalities of endocytosis develop very early in Alzheimer’s disease, well before clinical symptoms, and that variant forms of genes controlling endocytosis are frequently implicated as risk factors promoting Alzheimer’s. Endosomes — the membranous vesicles mediating endocytosis — start to swell abnormally in some neurons beginning even in infancy in Down syndrome – a developmental disability that almost invariably leads to early-onset AD. Research indicates that more than 75 percent of those with Down’s, aged 65 and older, have Alzheimer’s disease.

This image is a photo of a plastinated Alzheimer's brain.
Researchers found that, in Alzheimer’s and Down Syndrome, βCTF forms more rapidly on endosomes triggering a molecular pathway leading to loss of neurons involved with memory. The researchers discovered APPL1, a protein unrelated to amyloid precursor protein (APP) despite its similar acronym, directly links βCTF to a second protein, rab5, known to activate the molecular chain of events leading to neurodegeneration. Image is for illustrative purposes only.

The NYU Langone – NKI research team led by Ralph Nixon, MD, PhD, professor in the departments of psychiatry and cell biology at NYU Langone School of Medicine and director of the Center for Dementia Research at the Nathan S. Kline Institute for Psychiatric Research found that, in Alzheimer’s and Down Syndrome, βCTF forms more rapidly on endosomes triggering a molecular pathway leading to loss of neurons involved with memory. The researchers discovered APPL1, a protein unrelated to amyloid precursor protein (APP) despite its similar acronym, directly links βCTF to a second protein, rab5, known to activate the molecular chain of events leading to neurodegeneration. Lowering APPL1 levels in cells of individuals with Down syndrome abolished the abnormal endocytosis, indicating the vital role of APPL1 in this molecular cascade. The identification of APPL1 as the missing link in a well-described chain of events associated with very early Alzheimer pathology implies a direct contribution of ßCTF to Alzheimer’s disease development. Notably, a recently discovered APP mutation that uniquely lowers, rather than raising, risk for Alzheimer’s is believed to act by slowing the formation of ßCTF.

While the current findings do not place any more or less importance to Aß as a culprit and a target for Alzheimer’s therapy, they now underscore the importance of ßCTF as a key contributor to disease development. “It will be important to consider the role of βCTF in the design of future therapies for Alzheimer’s disease and in the interpretation of current clinical trials of BACE1 inhibitors. BACE1 inhibitor trials have been considered a test of the Aß/amyloid hypothesis but the primary action of these inhibitors is actually to block formation of ßCTF, the precursor of Aß,” said Ralph A. Nixon, MD, PhD.

About this Alzheimer’s disease research

Funding: Funding for the study was provided by the NIH/National Institute on Aging.

Source: Camy Sleeman – Nathan S. Kline Institute for Psychiatric Research
Image Credit: The image is in the public domain
Original Research: Full open access research for “Evidence that the rab5 effector APPL1 mediates APP-βCTF-induced dysfunction of endosomes in Down syndrome and Alzheimer’s disease” by S Kim, Y Sato, P S Mohan, C Peterhoff, A Pensalfini, A Rigoglioso, Y Jiang and R A Nixon in Molecular Psychiatry. Published online July 21 2015 doi:10.1111/desc.12323


Abstract

Evidence that the rab5 effector APPL1 mediates APP-βCTF-induced dysfunction of endosomes in Down syndrome and Alzheimer’s disease

β-Amyloid precursor protein (APP) and its cleaved products are strongly implicated in Alzheimer’s disease (AD). Endosomes are highly active APP processing sites, and endosome anomalies associated with upregulated expression of early endosomal regulator, rab5, are the earliest known disease-specific neuronal response in AD. Here, we show that the rab5 effector APPL1 (adaptor protein containing pleckstrin homology domain, phosphotyrosine binding domain and leucine zipper motif) mediates rab5 overactivation in Down syndrome (DS) and AD, which is caused by elevated levels of the β-cleaved carboxy-terminal fragment of APP (βCTF). βCTF recruits APPL1 to rab5 endosomes, where it stabilizes active GTP-rab5, leading to pathologically accelerated endocytosis, endosome swelling and selectively impaired axonal transport of rab5 endosomes. In DS fibroblasts, APPL1 knockdown corrects these endosomal anomalies. βCTF levels are also elevated in AD brain, which is accompanied by abnormally high recruitment of APPL1 to rab5 endosomes as seen in DS fibroblasts. These studies indicate that persistent rab5 overactivation through βCTF–APPL1 interactions constitutes a novel APP-dependent pathogenic pathway in AD.

“Evidence that the rab5 effector APPL1 mediates APP-βCTF-induced dysfunction of endosomes in Down syndrome and Alzheimer’s disease” by S Kim, Y Sato, P S Mohan, C Peterhoff, A Pensalfini, A Rigoglioso, Y Jiang and R A Nixon in Molecular Psychiatry. Published online July 21 2015 doi:10.1111/desc.12323

Feel free to share this neuroscience news.
Join our Newsletter
I agree to have my personal information transferred to AWeber for Neuroscience Newsletter ( more information )
Sign up to receive our recent neuroscience headlines and summaries sent to your email once a day, totally free.
We hate spam and only use your email to contact you about newsletters. You can cancel your subscription any time.
  1. Let’s break it down to simple English. Any type of brain cell damage can lead to this condition. To minimize brain cell damage, we need to remove or minimize exposure to harmful substances to include anesthesia’s, vaccines, prescription and over-the–counter medications, preservatives, dyes, and other non-food additives in our food, and avoid inhaling harmful substances such as bug sprays, perfumes/colognes, air fresheners, aerosol disinfectants, paint, paint thinners, glues, car exhausts fumes, as well as avoid eating food from cans or other bad packaging, and avoid eating cured meats or any foods containing sodium nitrates. We should also not use chemicals on our grass, play golf on chemically treated golf courses, avoid breathing in chemicals for killing mosquito’s or treating crops and quit drinking any chemical treated water. That is all good for a start. With the baby boomers coming of age, we need to be spending more money on funding care homes for the poor and working class.

  2. Remove Tylenol and all drugs that contain Tylenol from the market. Someone should check on the time that Tylenol was introduced, and then study the patients that suffered Alzheimer. The drug companies demonized aspirin, but what they did was flood the market with countless variations of medications that eliminated aspirin. I do not have Tylenol in my medicine cabinet.

  3. I appreciate all Alzheimer’s research. What I do not appreciate is how articles drop us off in the middle of the highway with no way to get home. I.e. Now that you have freaked us out, how about a cure? They do not have a pill to cure or prevent it..and probably will not for a while.

    Exercise- the vigorous type..getting your heart rate up with Interval training is excellent! Having a Non\Anti Inflammatory diet void of animal protein is another highly suggested lifestyle adoption. Adding coconut oil to your diet is a powerful tool helping to feed your brain all the proper fats and enzymes it needs to make connections.
    Turmeric, Garlic, Cinnamon, Oregano, are just a few items in G-d’s healing chest.

    These few steps will do more than any current pill in delaying and offsetting the disease. I have researched Alz a lot for the past 25 years and practiced lifestyle changes as my mother died of Alz.

    Take control of your health..this is true health care not sick care.

    1. @DonnG, I agree! I’ve also taken many steps (though not all that I should) to take Preventative steps in avoiding disease in general, but ALZ in particular, as I’ve watched (and cared for) my elderly mom degrading from it..

      PS, numerous times have I read educated comments on ALZ causes, mentioning the brain cells unmet need for “energy” as a possible root cause.

      Being the brain is made mostly of fat and apparently only (blood) glucose or ketones from fat metabolism are able to cross the blood-brain barrier to fuel the brain cells, and I have read that the ALZ-damaged cells can only uptake ketones, no longer glucose, I started my mom on coconut oil supplementation many years ago (somewhat out of my hands now as she’s in a nursing home) in a (late) attempt to provide that cellular ‘energy’ source. (she was always health-conscious but fell fully into that low-fat craze decades back, and I partially blame that). I myself consume coconut oil (and all those other wonderful herbs mentioned) every day in an attempt to Not go down that road..

      Anyway as I was browsing the (too technical for me) info above, the one line that jumped out seems related to this cellular-energy shortage theory: “endocytosis, the process by which cells absorb nutrients”. If these ‘nutrients’ aren’t there, in enough quantity, or able to be be absorbed at all, it would seem that this may have some correlation to the damaged cellular processes and eventually cells, and the disease.

      Best to all families out there with loved ones ravaged by this horrible disease. As DonnG said, -take control of your own health. At the very least, you are hedging your bet in a positive direction..

    2. Curious to me, is how this article actually slides backwards from research proven a year ago, that the Amyloid protein isn’t the culprit, and it doesn’t change through the degenerative processes of Alzheimer’s. The Tau protein, however does, and that is the invasive protein that tangles with the neurons in the brain and basically strangles them, and the Tau protein is the ONE that does show increases in quantity over the degenerative lifespan of the disease. My concern is, with the over 300 million dollars spent on research for Alzheimer’s how much of this is just grabbing a piece of that pie, and how much is real and current research? I have a personal and special interest in this research and knowing when they actually find something that works. I was diagnosed early onset just 8 months ago, lost my Mom in 2012 to this horrible disease, and now watch my wife struggle to help her Mom, as she deteriorates with this thing. Before I no longer could, I consulted with my neurologist, and wrote my 3rd book titled Painful Avoidance, my book on my journey with this horrible affliction, as well as my Mom’s and Mother-In-Laws. It is available of Amazon, in both paperback and Kindle versions. If it can help just one person understand this disease more, or help just one caregiver through this very hard time, then I have succeeded. God bless anyone touched by this terrible thing, a mind truly is a terrible thing to waste.

      1. Genetic link, need to explore the link. 3 generations, oldest in family line —–all very intelligent people.

        Loss of loved one preceded the diagnosis for Alzhiemer’s
        Grief and loss a factor.

        Possible relationship to head injury. What is so poignant is to have the person to say to you “I don’t remember” in a polite
        manly , and gentleman fashion. That has not disappeared.

        Medicines a possible exacerbation of symptoms——and loss of money via dishonest health worker.

      2. There isn’t a single culprit when it comes to AD. It is a multifactorial (both genetics and external insults) and likely combinatorial neurological disorder. These are PR articles that help secure both new grants and renewals. They often set people off in a panic. It’s unfortunate that we are still stuck technologically when it comes to the research and clinical studies on neurodegenerative diseases like AD. Mouse models are really just that. A model – that is very similar (perspectively) yet highly different (morphologically). Hence the unfortunate luck with most candidate therapies that enter the pipeline. I would even argue that a lot of “out of the box” research into the causes of AD are simply squeezed out by the Abeta people (the βaptists) and the Tau people (Tauists). Almost zero research goes into the peripheral organ system with no thought as to how their dysfunction may directly insult the brain when it comes to amyloid production. It’s convenient to not take into account that the genes that actually do cause early onset (under 60-65 yr) are expressed in every cell of your body. More perplexing is that ~85% of AD cases are not early onset and do not have any mutations to the known “culprit” genes. Alzheimer’s is a life long battle between you and the effects of aging. As we live longer – our chances of developing AD can be frightening to some.

Comments are closed.