Mechanism underlying Alzheimer-like damage in the brain of patients with
Down Syndrome elucidated

Date:
March 16, 2022
Source:
Temple University Health System
Summary:
Precisely why Alzheimer-like changes -- marked by the build-up of
harmful amyloid and tau proteins -- occur in the brain in Down
syndrome has been unclear. But now, in new research, scientists
show that reduced efficiency of a key protein transport system is
partly to blame.



FULL STORY ==========================================================================
Life expectancy for individuals with Down syndrome has grown in
recent decades, thanks in large part to progress in patient care and
treatment. But with survival into the fifth and sixth decades of life
now possible, increasing numbers of these individuals are affected by conditions linked to aging, among them impairments in thinking that are associated with the accumulation in the brain of atypical proteins better
known for their involvement in Alzheimer's disease.


========================================================================== Precisely why Alzheimer-like changes -- marked by the build-up of harmful amyloid and tau proteins -- occur in the brain in Down syndrome has been unclear. But now, in new research, scientists at the Lewis Katz School
of Medicine at Temple University show that reduced efficiency of a key
protein transport system is partly to blame. In analyses of human brain
tissue collected post-mortem, the researchers found that the so-called
retromer complex system, which plays a critical role in clearing damaged
and degraded proteins from neurons in the brain, operates at only about 50 percent of its usual efficiency in Down syndrome patients. The reduction
was linked specifically to the accumulation of pathogenic tau protein.

"The decline in protein transport via the retromer system is a lot like
a traffic jam, with the transporter stalling out and causing a major
back-up in the clearance of pathologic tau proteins, leaving them to
accumulate over time," explained Domenico Pratico`, MD, Scott Richards
North Star Foundation Chair for Alzheimer's Research, Professor in the Department of Neural Sciences, Director of the Alzheimer's Center at
Temple, and senior investigator on the new study.

"We also found that a major factor underlying tau accumulation is
diminished activity of the cathepsin-D enzyme, which resides within the retromer complex," Dr. Pratico` added. Cathepsin-D normally acts like a
pair of scissors, cutting up tau to facilitate its digestion and removal.

The study, published online in the journal Annals of Neurology, is the
first to connect reductions in retromer system efficiency and cathepsin-D activity to the accumulation of pathogenic tau in Down syndrome. The
findings are significant because they suggest that Alzheimer-like changes
are not strictly modulated by the extra copy of human chromosome 21 that
is characteristic of Down syndrome. Even though the extra chromosome
provides an additional copy of a gene known as amyloid precursor protein
(APP), which increases the risk of amyloid plaque formation, not all
Down syndrome patients develop dementia, implicating the involvement of
factors beyond genetics.

Dr. Pratico` and colleagues first measured the extent of tau pathology
in brain tissue from patients with Down syndrome and then assessed the relationship between the retromer core protein levels and the amount
of pathologic tau protein in young and aged individuals with Down
syndrome. They further compared the activity of cathepsin-D with the
amount of tau pathology in the same individuals.

The team's analyses uncovered an inverse relationship between the
emergence of tau pathology in Down syndrome and the levels of retromer
proteins and activity of cathepsin-D. Moreover, the team's observations
suggest that reduced levels of retromer proteins in young Down syndrome subjects sets the stage for the development of tau pathology later
in life.

"Overall, our data identify the retromer complex as a key regulator of pathogenic tau in Down syndrome, with evidence for the development of
tau pathology at a relatively young age," Dr. Pratico` said.

The results also identify the retromer system as a promising new target
for the treatment of Alzheimer's disease pathology in Down syndrome
patients. Drugs that target the retromer system, such as small chaperones,
have already been developed. In future work, Dr. Pratico` and colleagues
plan to explore these potential treatments in animal models that reproduce
most of the aspects of Down syndrome observed in humans.

"Using these existing therapeutics, we want to see if it is possible
to reverse amyloid plaque and pathological tau accumulation in animal
models," Dr.

Pratico` added. "If we are successful, we will have created an exciting opportunity to explore treatments in human patients with Down syndrome."
Other investigators who contributed to the new study include Mary
Elizabeth Curtis and Tiffany Smith, Alzheimer's Center at Temple, Lewis
Katz School of Medicine; and Daohai Yu, Department of Clinical Sciences,
Lewis Katz School of Medicine.

The study was funded in part by grants from the National Institutes of
Health (AG055707 and AG056689).


========================================================================== Story Source: Materials provided by Temple_University_Health_System. Note: Content may be edited for style and length.


========================================================================== Journal Reference:
1. Mary Elizabeth Curtis, Tiffany Smith, Daohai Yu, Domenico
Pratic�. Association of Retromer Deficiency and
Tau Pathology in Down Syndrome. Annals of Neurology, 2022; DOI:
10.1002/ana.26321 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2022/03/220316091719.htm

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