Genetically engineered mice suggest new model for how Alzheimer's causes dementia

Credit: Martha Sexton/public domain

Using a novel, newly developed mouse model that mimics the development of Alzheimer's disease in humans, Johns Hopkins researchers say they have been able to determine that a one-two punch of major biological "insults" must occur in the brain to cause the dementia that is the hallmark of the disease. A description of their experiments is published online in the journal Nature Communications.

For decades, Alzheimer's disease, the most common cause of dementia, has been known to be associated with the accumulation of so-called neurofibrillary tangles, consisting of abnormal clumps of a protein called tau inside brain , and by neuritic plaques, or deposits of a protein called beta-amyloid outside these cells along with dying nerve cells, in brain tissue.

In Alzheimer's disease, tau bunches up inside the nerve cells and beta-amyloid clumps up outside these cells, mucking up the nerve cells controlling memory, notes Philip C. Wong, Ph.D., professor of pathology at the Johns Hopkins University School of Medicine.

What hasn't been clear is the relationship and timing between those two clumping processes, since one is inside cells and one is outside cells, says lead and corresponding study author Tong Li, Ph.D., an assistant professor of pathology at Johns Hopkins. Prior studies of early-onset Alzheimer's disease have suggested that the abnormal accumulation of beta-amyloid in the brain somehow triggers the aggregation of tau leading directly to dementia and brain cell degeneration. But the new research from Li, Wong and colleagues suggests that the accumulation of beta-amyloid in and of itself is insufficient to trigger the conversion of tau from a normal to abnormal state. Instead, their studies show, it may set off a chain of chemical signaling events that lead to the "conversion" of tau to a clumping state and subsequent development of symptoms.

"For the first time, we think we understand that the accumulation of amyloid plaque alone can damage the brain, but that's actually not sufficient to drive the loss of nerve cells or behavioral and cognitive changes," Wong says. "What appears to be needed is a second insult—the conversion of tau—as well."

In humans, the lag between development of the and the inside can be 10 to 15 years or more, Li says, but because the lifetime of a mouse is only two to three years, current animal models that successfully mimic the appearance of beta-amyloid plaques did not offer enough time to observe the changes in tau.

To address that problem, the Johns Hopkins researchers genetically engineered a that used a tau fragment to promote the clumping of normal tau protein. They then cross-bred these mice with mice engineered to accumulate beta-amyloid. The result was a mouse model that developed dementia in a manner more similar to what happens in humans, Li says.

The researchers found during brain dissections of the animals that the presence of beta-amyloid plaque alone was not sufficient to cause the biochemical conversion of tau, the repeat domain of tau—the part of tau protein that is responsible for the conversion of normal tau to an abnormal state—alone was insufficient for the conversion of tau, beta-amyloid plaques must be present in the brain for the conversion of tau and the tau fragments could "seed" the plaque-dependent pathological conversion of tau.

One implication of the new research, Wong says, is to possibly explain why some drugs designed to attack the disease after the conversion of tau haven't worked. "The timing may be off," he says. "If you were to intervene in the time period before the conversion of tau, you might have a good chance of ameliorating the deficits, cell loss and ensuing consequence of the disease."

The work also suggests that combination therapy designed to prevent both the beta-amyloid plaque formation as well as pathological conversion of tau may provide optimal benefit for Alzheimer's disease, the researchers say. Their mouse model could be used to test new therapies.

An estimated 5.4 million Americans are living with Alzheimer's disease, according to 2016 statistics from the Alzheimer's Association. There is no cure, but there are some medications that may help stabilize cognition for a limited time or help with related depression, anxiety or hallucinations.

Explore further

PET points to tau protein as leading culprit in Alzheimer's

Journal information: Nature Communications

Citation: Genetically engineered mice suggest new model for how Alzheimer's causes dementia (2016, July 4) retrieved 23 July 2019 from
This document is subject to copyright. Apart from any fair dealing for the purpose of private study or research, no part may be reproduced without the written permission. The content is provided for information purposes only.

Feedback to editors

User comments

Jul 04, 2016
Amyloid plaques are NECESSARY but not SUFFICIENT.

1st: There is precipitation of Soluble Amyloid Beta 40-42 as Beta Amyloid Plaques in the presence of OXIDATIVE STRESS.

2nd: The Beta Amyloid Plaques so deposited, triggers an INFLAMMATORY REACTION; during which phase C-Reactive Protein and other mediators of inflammation rises in their levels.

3rd: The Inflammatory Response Triggered by the Beta Amyloid Plaques, so Deposited in the Brain, ultimately leads to the formation of hyper phosphorylated Tau proteins/neurofibrillary tangles that obstruct nutrient and oxygen supply to the brain cells and causing progressive ischemic atrophy.


The 1st Phase can be disrupted by ANTIOXIDANTS THAT CAN CROSS THE BLOOD BRAIN BARRIER: e.g. Astaxanthin, Glutathione, High Dose Resveratrol or Withania Somnifera root extract.

The 2nd Phase can be disrupted by NATURAL ANTI-INFLAMMATORY COMPOUNDS THAT CAN CROSS THE BLOOD BRAIN BARRIER: e.g. Astaxanthin, and Anatabine.

Jul 04, 2016
Okay. How does APOE4 play into your toy model?

Jul 04, 2016
OMG! More useless research by scientists seeking welfare for their needless research when the cause of Alzheimer's has already been known for decades! Alzheimer's is actually a simple biochemistry problem-long term deficit of glucose in the brain. i.e. diabetes type 3. Lack of glucose leads to insufficient ATP generation, and cholesterol and phospholipid shortage. Without these normal brain function simply isn't possible. Glucose deficit is made worse by aging, declining estrogen, testosterone, thyroid and melatonin, aging, free radicals, cardiovascular disease, MSG, aspartame, trans-fats, acrylamide, sodium nitrite, plastics, industrial chemicals, pesticides, herbicides, fungicides, air pollution, prescription drugs, , vaccines, inflammation, chronic systemic infections, homocysteine, hypomethylation, heavy metals, diabetes type II, AGE's, apoE-4 isoform, vitamin/mineral deficits, etc. All of these pathways have already been worked out, but not shared with American public.

Jul 05, 2016
APOE4 contributes towards the aggregation of Amyloid and so will play into the 1st phase:-The precipitation of Soluble Amyloid Beta 40-42 as Beta Amyloid Plaques in the presence of OXIDATIVE STRESS.

APOE4 increases a person's risk of developing the disease; however, inheriting an APOE ε4 allele does not mean that a person will definitely develop Alzheimer disease.

APOE at the molecular level helps in the synthesis of apolipoprotein E, which is a cholesterol carrier in the brain, helping in amyloid aggregation and the clearing of deposits from the parenchyma of the brain.

Jul 07, 2016
this and speaking in fragmented sentences or interjecting, not necessarily inappropriate, but not quite the right word or phrase; you shake it off as "silly grandpa." Then slowly you notice the drifting off in conversation or staring blankly into space that you rationalize they are just deep in thought.

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more