New Role of Apolipoprotein E4 Variant in Alzheimer's Disease Suggests Possible Therapeutic Target

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Highlights :

• ApoE4 variant increases brain damage that is caused by toxic tangles of a different Alzheimer's-associated protein named tau.
• ApoE4 is a variant of the ApoEgene that causes accumulation of amyloid B plaques implicated in Alzheimer's disease.
• The tau protein gets hyperphosphorylated in AD forming neurofibrillary tangles.

The presence of ApoE4 increases the brain damage caused by toxic tangles of a different Alzheimer's-associated protein named tau, concluded a study led by researchers at Washington University School of Medicine in St. Louis. Tau tangles do very little harm to brain cells when ApoE is not present. The study is published in the journal Nature.

Reason for Study

Mere accumulation of amyloid beta clumps does not kill brain cells or produce the characteristic Alzheimer's symptoms such as memory loss and confusion.

The findings suggest that targeting ApoE could help prevent or treat the brain damage present in Alzheimer's disease, for which there are currently no effective therapies.

‘The ApoE4 variant that is known to increase risk of Alzheimer�s disease, increases brain damage caused by toxic tangles of a different Alzheimer�s-associated protein named tau. This suggests it can become a possible therapeutic target.’

"Once tau accumulates, the brain degenerates," said senior author David Holtzman, MD, the Andrew B. and Gretchen P. Jones Professor and head of the Department of Neurology. "What we found was that when ApoE is there, it amplifies the toxic function of tau, which means that if we can reduce ApoE levels we may be able to stop the disease process."

Study

To find out what effect ApoE variants have on tauopathies, Holtzman and graduate student Yang Shi and their colleagues conducted the study on genetically modified mice that carry a mutant form of human tau that was to forming toxic tangles.

They utilized mice that lacked their own version of the mouse ApoEgene or replaced it with one of the three variants of the human ApoEgene. The three variants of the ApoEgene play different roles

• ApoE2 is protective in nature
• ApoE3 is the more common one found in a majority of people
• ApoE4 increases the risk of developing Alzheimer's

Results of the Study

The mice were examined at the age 9 months, when it was detected that the ones carrying human ApoE variants had widespread brain damage.

Hippocampus and entorhinal cortex, important for memory, were shrunken

Fluid-filled space of the brain had enlarged where the dead cells had been. ApoE4 expressing mice exhibited the most severe neurodegeneration

ApoE2 expressing mice exhibited the least severe neurodegeneration the least. Mice that lacked ApoE entirely showed virtually no brain damage.

Immune cells in the brains of mice with ApoE4 turned on a set of genes related to activation and inflammation much more strongly than those from ApoE3 mice. Immune cells from mice lacking ApoE were barely activated.

"ApoE4 seems to be causing more damage than the other variants because it is instigating a much higher inflammatory response, and it is likely the inflammation that is causing injury," Holtzman said. "But all forms of ApoE - even ApoE2 - are harmful to some extent when tau is aggregating and accumulating. The best thing seems to be in this setting to have no ApoE at all in the brain."

To find out whether ApoE in people similarly exacerbates neuronal damage triggered by tau, the researchers collaborated with Bill Seeley, MD, from the University of California, San Francisco. Seeley identified autopsy samples from 79 people who had died from tauopathies other than Alzheimer's disease in the past 10 years. The researchers examined each brain for signs of injury and noted the deceased's ApoE variants. They found that, at the time of death, people with ApoE4 had more damage than those that lacked ApoE4.

ApoE transports cholesterol around the body via the bloodstream. Individuals who lack a functional ApoE gene have very high cholesterol levels and, if untreated, die young of cardiovascular disease. However, the lack of ApoE in their brains creates no obvious problems.

"There are people walking around who have no ApoE and they're fine cognitively," Holtzman said. "It doesn't appear to be required for normal brain function."

This study suggests that decreasing ApoE specifically in the brain could slow or block neurodegeneration, even if tau tangles have already accumulated in the brain.

"Assuming that our findings are replicated by others, I think that reducing ApoE in the brain in people who are in the earliest stages of disease could prevent further neurodegeneration," Holtzman said.

Alzheimer's Disease (AD)

Alzheimer's is a neurodegenerative disease and the most common form of dementia, accounting for 60 to 80 percent of dementia cases. Dementia is a condition characterized by memory loss and other cognitive abilities that are serious enough to interfere with daily life.

Alzheimer's disease

• Is not a normal part of aging
• Is a progressive disease, that worsens over time
• Affects one in 10 people over age 65
• Has no cure, but treatments for symptoms are available

Causes for AD

• Early onset familial AD, that has an onset before age 64 has a genetic cause. Mutations in one of three genes have been implicated and it has an autosomal (not sex-linked) dominant inheritance.
• The oldest hypothesis is the "cholinergic hypothesis" that states that AD is caused by a deficiency in the production of acetylcholine, a vital neurotransmitter.
• AD was identified as a protein misfolding disease, when in 1991 the amyloid hypothesis postulated that accumulation of abnormally folded extracellular amyloid beta (Aβ) deposits found in the brains of AD patients are the fundamental cause of the disease.
• AD is also considered to be a part of a family of diseases called tauopathies that are characterized by the presence of abnormal aggregation of the tau protein.

Several degenerative processes are known to occur in the brains of people with Alzheimer's disease.

Apolipoprotein E4 (ApoE4)

ApoE proteins are a class of apolipoproteins essential for the normal break down of triglyceride-rich lipoprotein constituents. They are mainly produced by astrocytes in the central nervous system, and are the principal cholesterol carriers to neurons via members of the low density lipoprotein receptor gene family, ApoE receptors.

This protein is involved in Alzheimer's disease and cardiovascular disease. The E4 variant was identified as the largest known genetic risk factor for late-onset sporadic AD in a variety of ethnic groups nearly a quarter century ago. Having the variant increases a person's chances of developing the neurodegenerative disease by up to 12 times. When the ApoE4 protein is present, clumps or plaques of a protein called amyloid beta (Ab) start getting accumulated the brain.

For decades, most researchers ignored the leading genetic risk factor for Alzheimer's disease. Now, that is set to change.

Tau Protein

The tau protein expressed in neurons is normally regulated by phosphorylation and is bound to and acts to stabilize microtubules in the cell cytoskeleton.

In neurodegenerative diseases like AD, hyperphosphorylated tau accumulates as paired helical filaments that in turn aggregate into masses known as neurofibrillary or gliofibrillary (in neurons or glial cells) tangles and as dystrophic neurites associated with amyloid plaques. When tangles get formed, the microtublues disintegrate destroying the cell's cytoskeleton, which collapses the neuron's transport system. This may initially result in malfunctions in biochemical communication between neurons and later in the death of the cells.

Thus, inhibition of abnormal tau hyperphosphorylation can offer a promising therapeutic target for AD and related tauopathies.

Treatment for AD

While the current treatment methods for AD cannot stop the progression of the disease, they prevent dementia symptoms from getting worse and improve quality of life for the affected and their caregivers.

There are two classes of drugs used for treatment.

• Cholinesterase inhibitors that prevent the enzyme from breaking down a neurotransmitter in the brain called acetylcholine (ACh). In normal individuals, cholinesterase prevents excess post-synaptic and muscle activation by ACh by breaking it down.
• N-methyl D-aspartate (NMDA) receptor inhibitors that prevent glutamate from attaching to the NMDA receptors and thus inhibit their overstimulation by glutamate.

New targets and alternative therapeutic strategies that can stop the progression of the disease have to be developed to treat AD. As ApoE genotype determines AD risk, and ApoE has crucial roles in cognition, targeting it might offer an attractive alternative target for AD therapy.

Drugs in development may change the physical structure of the ApoE4 protein to behave more like the protective ApoE2 protein. The gene therapy approach attempts to insert ApoE2 genes into the brains of people with APOE4 genes.

So far, investigational therapies for Alzheimer's disease have focused on amyloid beta or tau, and none of them have changed the trajectory of the disease. Targeting ApoE has not yet been tried, according to Holtzman.

References:

1. Liu C-C, Kanekiyo T, Xu H, Bu G. Apolipoprotein E and Alzheimer disease: risk, mechanisms, and therapy. Nature reviews Neurology. 2013;9(2):106-118.doi:10.1038/nrneurol.2012.263.
2. Iqbal K, Liu F, Gong C-X, Grundke-Iqbal I. Tau in Alzheimer Disease and Related Tauopathies. Current Alzheimer research. 2010;7(8):656-664.
3. Alzhiemer's Diseases - (https:en.wikipedia.org/wiki/Alzheimer%27s_disease)

Source: Medindia

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