Several genes and their protein products are already known to be
implicated in Alzheimer's disease pathology. A gene coding for a
protein that turns off neurotransmission signaling, which contributes to
Alzheimer's disease (AD), has been identified by a Tel Aviv University study.
The gene, called RGS2 (Regulator of Protein Signaling 2), has never
before been implicated in AD. The researchers report that lower RGS2
expression in AD patient cells increases their sensitivity to toxic
effects of amyloid-β. The study, published in Translational Psychiatry
may lead to new avenues for diagnosing Alzheimer's disease - possibly a
blood test - and new therapies to halt the progression of the disease.
‘Lower expression of a neurotransmitter gene, called RGS2 (Regulator of Protein Signaling 2), in Alzheimer's disease patient cells increases their sensitivity to toxic effects of amyloid-β.’
The research was led by Dr. David Gurwitz of the Department of Human
Molecular Genetics and Biochemistry at TAU's Sackler School of Medicine
and Prof. Illana Gozes, the incumbent of the Lily and Avraham Gildor
Chair for the Investigation of Growth Factors; Head of the Elton
Laboratory for Molecular Neuroendocrinology at TAU's Sackler School of
Medicine; and a member of TAU's Adams Super Center for Brain Studies and
TAU's Sagol School of Neuroscience. Also participating in the research
were their PhD student Adva Hadar and postgraduate student Dr. Elena
Milanesi, in collaboration with Dr. Noam Shomron of the Department of
Cell and Developmental Biology at TAU's Sackler Faculty of Medicine and
his postgraduate student Dr. Daphna Weissglas; and research teams from
Italy and the Czech Republic.
Identifying the suspect
"Alzheimer's researchers have until now zeroed in on two specific
pathological hallmarks of the chronic neurodegenerative disease:
deposits of misfolded amyloid-β (Aβ) peptide plaques, and phosphorylated
tau protein neurofibrillary tangles found in diseased brains," Dr.
Gurwitz said. "But recent studies suggest amyloid-β plaques are also a
common feature of healthy older brains. This raises questions about the
central role of Aβ peptides in Alzheimer's disease pathology."
The researchers pinpointed a common suspect - the RGS2 gene - by
combining genome-wide gene expression profiling of Alzheimer's disease
blood-derived cell lines with data-mining of previously published gene
expression datasets. They found a reduced expression of RGS2 in
Alzheimer's disease blood-derived cell lines, then validated the
observation by examining datasets derived from blood samples and
post-mortem brain tissue samples from Alzheimer's patients.
"Several genes and their protein products are already known to be
implicated in Alzheimer's disease pathology, but RGS2 has never been
studied in this context," Dr. Gurwitz said. "We now propose that whether
or not Aβ is a primary culprit in Alzheimer's disease, neuroprotective
mechanisms activated during early disease phases lead to reduced RGS2
Sensitizing brain neurons to potential damage
The new TAU study furthermore proposes that reduced RGS2 expression
increases the susceptibility of brain neurons to the potentially
damaging effects of Aβ.
"We found that reduced expression of RGS2 is already noticeable in
blood cells during mild cognitive impairment, the earliest phase of
Alzheimer's," Dr. Gurwitz observed. "This supported our theory that the
reduced RGS2 expression represents a 'protective mechanism' triggered by
ongoing brain neurodegeneration."
The team further found that the reduced expression of RGS2 was
correlated with increased Aβ neurotoxicity. It acted like a double-edged
sword, allowing the diseased brain to function with fewer neurons,
while increasing damage to it by accumulating misfolded Aβ.
"Our new observations must now be corroborated by other research
groups," Dr. Gurwitz concluded. "The next step will be to design early
blood diagnostics and novel therapeutics to offset the negative effects
of reduced expression of the RGS2 protein in the brain."