Age-Related Degeneration and Alzheimer’s Disease Link Discovered

Aging causes aggregation of protein which triggers amyloid-β plaque aggregation, that is a characteristic feature of Alzheimer's disease.

Highlights:

Protein aggregation is a common feature of aging and this aggregation is an important risk factor for neurodegenerative diseases, such as Alzheimer’s disease.
Several of these aggregation-prone proteins are found as minor components in hallmark aggregates associated with the disease, such as amyloid-β plaques or neurofibrillary tangles, findings reveal.
Changes in protein aggregation occurring during middle-age initiated Aβ plaque aggregation.

The changes in the proteins associated with aging were directly connected to the protein formation that is commonly associated with neurodegenerative conditions like Alzheimer's disease.

A team of researchers from the German Center for Neurodegenerative Diseases and Hertie Institute can be credited with the findings.

Alzheimer’s disease - Causes, Symptoms, Diagnosis, Stages, Types, Prevention, Prognosis & Treatment
Alzheimer's disease is a progressive neurodegenerative disease affecting memory and thinking and making the person increasingly dependent on others.

‘Age-dependent protein aggregates are shown to be critical for the pathogenesis of neurodegenerative conditions like Alzheimer's disease, and could therefore be used as possible therapeutic targets to alleviate the disease.’

The aggregation of proteins is common in neurodegenerative diseases.

These aggregated proteins are formed when misfolded proteins clump together to form the highly intractable structure. These misfolded proteins have lost the elaborate but recognizable shape that dictates their function.

The findings by Drs. Della David and Frank Baumann show that proteins aggregate increasingly with age, even in the absence of the disease.

Quiz On Alzheimer’s Disease
Alzheimer’s disease (AD) is the most common form of dementia. Participate in this quiz to find out how much you know about this debilitating disease.

What is Alzheimer’s Disease?

Alzheimer’s disease is a brain disorder that leads to progressive loss of cognition, including memory and thinking skills. It affects people who are in their mid-60's and is the main cause of dementia among older individuals. Around 60%-80% of dementia cases can be attributed to Alzheimer’s.

How Western Diet Triggers Amyloid Beta Plaque Formation in the Brain
Western diet significantly increases the activity of microglia, which function as the brain’s immune cells causing plaque formation in the brain.

Dementia causes loss of memory, thinking skills, and reasoning. It interferes with a person’s daily life and activities.

In America, around 5 million people have Alzheimer's disease and around 200,000 cases are found in people below 65 years of age. It is the 6th leading cause of death in the U.S.

'Memory Proteins' Cause Dementia in Alzheimer's Disease
The combination of accumulation of amyloid and low levels of protein NPTX2 is responsible for the cognitive failure in Alzheimer's disease.

Around a decade before the commencement of symptoms, changes like abnormal deposits of proteins occur in the brain. These lead to the formation of amyloid plaques and tau tangles throughout the brain. These then lead to the loss of function and death of neurons, which eventually leads to memory problems, changes in personality and other symptoms of the disease.

Memory loss is the one of the first signs of cognitive impairment related to Alzheimer’s disease.

As the disease advances, it can cause severe symptoms like temporal and spatial disorientation, changes in behavior and mood, confusion and finally difficulty in walking, talking and swallowing.

Study

For the study, the research team investigated whether aging seeds (which are proteins that clump together with age to form aggregates) could induce the aggregation of Amyloid beta (Aβ) plaques, through a phenomenon called cross-seeding.

In cross-seeding, different protein aggregates can induce the aggregation of another.

The test subject for the study was C. elegans, which has limited number of cells.

The testing showed that in vitro aggregation of Aβ plaque could be induced by age-dependent protein aggregates. This was particularly true for older C. elegan specimens where the age-dependent protein aggregates induced Aβ aggregation through cross-seeding.

How were the Tests Verified?

When the tests were conducted in vitro on mouse brain extracts of different age groups, the results showed a similar outcome : age-dependent protein aggregates induced Aβ plaque aggregation through cross-seeding.

Some proteins that warranted further investigation were identified by performing a protein count via mass spectrometry for C. elegans.

It showed that the proteins that aggregate increasingly after middle-age were promising candidates for cross-seeding activity. These proteins are present as minor components in disease-associated aggregates.

One of these proteins, PAR-5, that are aggregation-prone, can induce Aβ toxicity in vivo.

It showed that Aβ toxicity in C. elegans was accelerated by a combination of overexpressed PAR-5 with Aβ plaque accumulation.

These findings highlight that certain minor components may qualify as proteins that "could be more prone to aggregate in specific brain regions and thus help the generation and spreading of disease-associated seeds in certain brain circuits."

Conclusion

This study shows that aging associated changes in protein conformations may be responsible for Alzheimer's disease through Aβ aggregation and toxicity.

The study team suggests that the mapping of the aggregating proteins in both healthy and neurodegenerative human brain samples will help identify "which aging seeds need to be looked at and whether certain aging seeds would be more prone to seed or associate with specific disease types in specific anatomical areas”.

The findings are published in the Frontiers in Aging Neuroscience.

References:

Alzheimer's Disease Fact Sheet - (https://www.nia.nih.gov/alzheimers/publication/alzheimers-disease-fact-sheet)
What Is Alzheimer’s? - (http://www.alz.org/alzheimers_disease_what_is_alzheimers.asp)
Della David et al. Age-dependent protein aggregation initiates amyloid-β aggregation. Frontiers in Aging Neuroscience; (2017) doi: 10.3389/fnagi.2017.00138

Source-Medindia