Key mechanisms behind synapse degeneration in Alzheimer's brain
discovered
Targeting newly identified signaling pathway holds promise for treatments
of neurodegenerative disorders

Date:
August 18, 2021
Source:
University of California - San Diego
Summary:
Neurobiologists have uncovered the long-sought-after mechanisms
behind the maintenance and decline of key synapses implicated
in brain disorders such as Alzheimer's disease. The researchers
identified the main components driving amyloid beta-associated
synapse degeneration, which is found in the brains of people
with Alzheimer's. The findings suggest an alternative approach
to addressing neurodegenerative disorders: protect synapses by
directly blocking the toxic actions of amyloid beta.



FULL STORY ========================================================================== Healthy adult brains are endowed with a vast number of synapses,
structures that relay signals across nerve cells to enable communications, information processing and storage throughout the nervous system. Apart
from dynamic periods when the brain is learning new information or
skills, the number of the "glutamatergic" synapses, the major type
of synapses that neurons use to activate each other, largely remains
constant in adults.


==========================================================================
In brain disorders such as Alzheimer's, these synaptic connections,
which hold our precious memories, are known to break down too early and disappear. This synapse degeneration is thought to start long before
the loss of memory and accelerate as diseases progress. The causes of
synapse degeneration in neurodegenerative disorders has not been well understood, mainly because scientists have not yet unraveled the key
mechanisms that normally hold together these tiny structures (an average
of one micrometer in diameter) throughout our lifetime.

Neurobiologists at the University of California San Diego have now
uncovered the long-sought-after mechanisms behind the maintenance of glutamatergic synapses. Based on this fundamental discovery, Division
of Biological Sciences Postdoctoral Scholar Bo Feng, Professor Yimin
Zou and their colleagues have identified the main components driving
amyloid beta-associated synapse degeneration. Amyloid beta are peptides
of 36-43 amino acids derived from the amyloid precursor protein (APP)
and are the main component of amyloid plaques found in the brains of
people with Alzheimer's disease.

Despite tremendous efforts, drug discovery for Alzheimer's disease has
not been successful. So far, the main approaches have been to either
reduce amyloid beta production or clear amyloid beta plaques. The new
discovery from UC San Diego researchers, published in Science Advances
on August 18, 2021, suggests an alternative approach further downstream: protect synapses by directly blocking the toxic actions of amyloid beta.

Glutamatergic synapses are highly polarized structures with a presynaptic
part from one nerve cell and a postsynaptic part from another. This type
of polarity ensures the proper direction of information flow. Zou's lab
had previously found that during brain development the highly polarized synaptic structures are assembled by components of the planar cell
polarity (PCP) pathway: a powerful signaling pathway that polarizes
cell-cell junctions along the tissue plane. Using super resolution
microscopy, the researchers detected the precise location of these
same PCP signaling components, called Celsr3, Frizzled3 and Vangl2,
in the glutamatergic synapses in the adult brain. They then found
that removing these components, essential for the initial assembly
of synapses from adult neurons, can dramatically alter the number of
synapses. These surprising discoveries suggest that the overall synapse
number in a normal brain is maintained by a fine balance between Celsr3
(which stabilizes synapse) and Vangl2 (which disassembles synapses).

Curious about whether these components are involved in synapse
degeneration, they tested whether amyloid beta, a key driver of synapse
loss in Alzheimer's disease, affects the function or interaction of
these proteins. In a series of experiments, they showed that amyloid
beta oligomers bind to Celsr3 and allow Vangl2 to more effectively
disassemble synapses, likely by weakening the interactions between Celsr3
and Frizzled3.



========================================================================== "This is as if amyloid beta has long discovered the Achilles' heel of
our synapses," said Zou, a professor in the Section of Neurobiology,
Division of Biological Sciences.

When the researchers removed Vangl2 from neurons, they found that amyloid
beta can no longer cause synapse degeneration both in neuronal cultures
and in animals exposed to amyloid beta oligomers. Ryk, a regulator of
the PCP pathway that interacts with Frizzled3 and Vangl2, is also found
present in the adult synapses and functions in the same way as Vangl2
to mediate synapse disassembly. Blocking Ryk using function-blocking
antibodies can protect synapses from amyloid beta-induced degeneration,
the researchers found.

To further test the hypothesis that this fundamental signaling pathway
is a primary target of synapse degeneration in Alzheimer's disease,
the Zou lab used 5XFAD mice, a well-known mouse model of amyloid beta pathology. This transgenic mouse carries five human mutations that
cause Alzheimer's disease and therefore shows severe symptoms of synapse degeneration and cognitive function loss. They found that removing Ryk
by gene knockout from adult neurons protected synapses and preserved
cognitive function of 5XFAD mice. Infusion of the function blocking the
Ryk antibody also protected synapses and preserved cognitive function in
5XFAD mice, suggesting the Ryk antibody is a potential therapeutic agent.

These exciting results suggest that the PCP pathway is a direct target
of amyloid beta-induced synapse loss in Alzheimer's disease.

"As amyloid beta pathology and synapse loss usually occurs in early stages
of Alzheimer's disease, even before cognitive decline can be detected,
early intervention, such as restoring the rebalance of the PCP pathway,
will likely be beneficial for Alzheimer's patients," said Zou.

Neuroinflammation, reflected by astrocyte and microglia activation, is
also a hallmark of Alzheimer's pathology, which can be induced by amyloid
beta accumulation and is known to accelerate synapse loss. Excitingly,
the Zou lab found that the Ryk antibody can also block the activation of astrocytes and microglia in 5XFAD mice. Although they cannot distinguish whether this is due to the indirect effect of synapse protection or
the blockage of Ryk functions in inflammation, or both, Zou believes
that the results are consistent with the improved cognitive behavior and further support Ryk as a potential therapeutic target for both protecting synapses and reducing inflammation in Alzheimer's disease.

"This discovery may be applicable to synapse degeneration in general as
the PCP components may be the direct synaptic targets mediating synapse
loss in other neurodegenerative disorders, such as Parkinson's disease
and Amyotrophic Lateral Sclerosis (Lou Gehrig's disease)," said Zou.

The research was funded by the National Institutes of Health (RO1
MH116667).

Airyscan confocal microscopy imaging was performed at the UC San Diego
School of Medicine Light Microscopy Facility (P30 NS047101).

========================================================================== Story Source: Materials provided by
University_of_California_-_San_Diego. Original written by Mario
Aguilera. Note: Content may be edited for style and length.


========================================================================== Journal Reference:
1. Bo Feng, Andiara E. Freitas, Lilach Gorodetski, Jingyi Wang,
Runyi Tian,
Yeo Rang Lee, Akumbir S. Grewal, Yimin Zou. Planar cell polarity
signaling components are a direct target of b-amyloid-associated
degeneration of glutamatergic synapses. Science Advances, 2021;
7 (34): eabh2307 DOI: 10.1126/sciadv.abh2307 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2021/08/210818153647.htm

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