- 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
‘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
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.
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.
causes loss of memory,
thinking skills, and reasoning. It interferes with a person's daily life and
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.
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.
is the one of
the first signs
of cognitive impairment related to Alzheimer's disease.
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
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
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."
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
- 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)