Targeting the brain's immune cells may help prevent or treat Alzheimer's disease

Date:
December 1, 2021
Source:
Weill Cornell Medicine
Summary:
A gene mutation linked to Alzheimer's disease alters a signaling
pathway in certain immune cells of individuals with the disease,
according to a new study. The team also found that blocking
the pathway -- with a drug that's currently being tested in
cancer clinical trials -- protects against many features of the
condition in a preclinical model. The results could lead to new
strategies to block the development of Alzheimer's disease or slow
its progression.



FULL STORY ==========================================================================
A gene mutation linked to Alzheimer's disease alters a signaling pathway
in certain immune cells of individuals with the disease, according to a
new study by scientists at Weill Cornell Medicine. The team also found
that blocking the pathway -- with a drug that's currently being tested in cancer clinical trials -- protects against many features of the condition
in a preclinical model. The results could lead to new strategies to
block the development of Alzheimer's disease or slow its progression.


==========================================================================
The study, published Dec. 1 in Science Translational Medicine, focused
on microglia, immune cells of the central nervous system that are the
first to respond when something goes wrong in the brain. Studies have identified many genetic variants linked to Alzheimer's disease that
are highly expressed in microglia, providing compelling evidence that alterations within these cells may play a role in the disease's onset
and progression.

"Microglia are guardians of the brain under healthy conditions, but
can turn detrimental in disease conditions. Our goal is to identify how
they become toxic and contribute to Alzheimer's disease pathogenesis and whether we can identify immune modulators to reverse the toxicity without diminishing their normal protective function," said senior author Dr. Li
Gan, director of the Helen and Robert Appel Alzheimer's Disease Research Institute and the Burton P.

and Judith B. Resnick Distinguished Professor in Neurodegenerative
Diseases in the Feil Family Brain and Mind Research Institute at Weill
Cornell Medicine.

Alzheimer's disease is the most prevalent neurodegenerative disease in
ageing, affecting approximately 46 million people worldwide. Theories
point to a number of potential causes, including age-related changes in
the brain, along with genetic, environmental, and lifestyle factors. These
lead to the accumulation of toxic proteins in the brain -- and according
to recent evidence, immune system changes -- that result in loss of
neurons and their connections.

To examine how the brain's immune cells may contribute to Alzheimer's
disease, Dr. Gan and her colleagues first established the molecule
fingerprint of individual microglia in the brains of patients with
Alzheimer's disease who carry a mutation in the TREM2 gene that markedly elevates individual's risk for developing Alzheimer's disease. TREM2
is a receptor mainly expressed by microglia in the brain, and among
other functions, it signals through an enzyme named AKT to modulate inflammation and metabolism.

The team then established a mouse model by combining two strains; one
that carries the AD-linked mutation in the TREM2 gene and another that
exhibits Tau aggregates, one of the major pathological hallmarks in
Alzheimer brains. Both patients and mice with the mutation demonstrated memory-related deficits, and their microglia expressed high levels
of inflammatory molecules and exhibited an overactive AKT signaling
pathway. In the mice, inhibiting AKT with a drug called MK-2206 reversed
the inflammatory properties of microglia and protected against synaptic toxicity -- a type of damage to the brain's neurons that is a hallmark
of Alzheimer's disease.

Importantly, because AKT signaling also contributes to the pathogenesis
of many types of cancer, MK-2206 is currently being evaluated in multiple cancer clinical trials. Therefore, the safety of the drug is already
under investigation.

"We identified a small molecule compound that has been tested in patients
with cancer, readily enters the brain, potently modulates the brain's
immune responses, and protects against synaptic loss in animal models of Alzheimer's disease," Dr. Gan said. "Our findings support further study of
this compound as a potential therapy for Alzheimer's disease." Dr. Li Gan
is a co-founder with equity and consultant for Aeton Therapeutics, Inc.

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


========================================================================== Journal Reference:
1. Faten A. Sayed, Lay Kodama, Li Fan, Gillian K. Carling, Joe
C. Udeochu,
David Le, Qingyun Li, Lu Zhou, Man Ying Wong, Rose Horowitz, Pearly
Ye, Hansruedi Mathys, Minghui Wang, Xiang Niu, Linas Mazutis,
Xueqiao Jiang, Xueting Wang, Fuying Gao, Matthew Brendel, Maria
Telpoukhovskaia, Tara E.

Tracy, Georgia Frost, Yungui Zhou, Yaqiao Li, Yue Qiu, Zuolin
Cheng, Guoqiang Yu, John Hardy, Giovanni Coppola, Fei Wang,
Michael A. DeTure, Bin Zhang, Lei Xie, John Q. Trajnowski,
Virginia M. Y. Lee, Shiaoching Gong, Subhash C. Sinha,
Dennis W. Dickson, Wenjie Luo, Li Gan. AD-linked R47H- TREM2
mutation induces disease-enhancing microglial states via AKT
hyperactivation. Science Translational Medicine, 2021; 13 (622)
DOI: 10.1126/scitranslmed.abe3947 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2021/12/211201145309.htm

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