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Over a century ago, Alois Alzheimer
first discovered Alzheimer’s Disease (AD), an irreversible progressive illness
that causes a decline in memory and a loss of cognitive function and
eventually, death. The diagnosis of AD is based on brain atrophy and
characteristic neuropathologic markers, which are intracellular neurofibrillary
tangles that contain the tau protein and extracellular amyloid plaques that
have beta amyloid deposits (Ab).

AD is the most common form of dementia, accounting for 60-80% of all cases. The
largest risk factor for AD is age, and presently, there is no cure for the
disease. The extremely high costs for care of AD patients ($259 billion yearly)
and the high prevalence of AD in older populations makes identifying treatments
to prevent or cure AD a priority. Currently, the National Alzheimer’s Project
Act (NAPA) has a goal in place to identify an effective treatment for
Alzheimer’s by 2025.

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Along with age, genetic variation
is also an important factor in risk of this disease, and about 70% of AD cases
are heritable (Avramopoulos, 2009). Research in genetic studies have allowed
for advances in identifying genetic risk factors involved in the onset of AD.

One of these genetic risk factors is a mutation in the triggering receptor
expressed on myeloid cells-2 (TREM2). Several GWAS studies have identified this
risk gene to increase the risk of AD 3-4 fold. TREM2 is an innate immune
receptor and is expressed on myeloid cells, including microglia and is part of
the immunoglobin family. Microglia are the primary innate immune cells of the
brain because they phagocytose and rid pathogens, toxins, and debris (3). Being
that TREM2 is a newly discovered risk gene, little is known about the exact
functions (3). However, TREM2 has been found to decrease inflammatory response
by repressing cytokine production and secretion by pairing with DAP12, a
signaling adapter. TREM2 also positively regulates phagocytic functions of the
myeloid cells (3). Loss of function mutations are most likely the single nucleotide
polymorphism (SNP) associated with the risk of AD. Homozygous loss-of-function
mutations of TREM2 correspond to a development of early-onset presenile dementia
with cysts on bones, called Nasu-Hakola disease (NHD) (3). Frontotemporal
dementia (FTD) that cause seizures and corpus callosum atrophy can also be
caused by homozygous TREM2 mutations (3). Heterozygous TREM2 point mutations
can decrease ligand binding or cell surface expression correspond to a
decreased number of microglia around beta amyloid plaques (ref). The lack of
microglia causes an increase in the number of phosphorylated Tau proteins
(ref). These mutations cause a 2-fold increase in brain atrophy, increase the
risk of AD 3-fold, and decrease the age of AD onset by about 3-6 years.

Previous studies on TREM2’s role in
AD pathology have had opposing results. For instance, one such study yielded
that TREM2 upregulation by viral vector expression resulted in amelioration of
beta amyloid deposits, neuroinflammation, and neuronal reduction as well as an
improvement in cognitive function in young APP/PS1 mice, but did not affect the
odler mice (6,7). Their results suggest that upregulating TREM2 may be a
protective factor from AD progression by changing microglia functioning (6). Another
study showed that missense mutations of TREM2 associated with frontotemporal
dementia (FTD) and FTD-like syndrome decrease the phagocytic activity of cells
that express TREM2, which suggests that these mutations are loss of function
(8). Conversely, Wang et al. shows that lack of TREM2 in APP/PS1 mice lead to nonfunctioning
microglial responses, causing apoptosis instead of activated and proliferating
responses (9). This TREM2 deficiency causes amyloid buildup. Another study
shows that deleting TREM2 from APP/PS1 mice genetically ameliorates amyloid
pathology in amyloid depositing transgenic mice (10). We predict that
investigating TREM2 further might lead to a successful therapeutic target for
AD. Research is continually searching for explanations of the conflicting
results of previous studies on TREM2.

TREM2 antibodies have been accounted for through in vivo and in vitro studies
that activate TREM2 receptors. These antibodies have been developed by Dr.

Rosenthal and colleagues. Specifically, the activating antibody for TREM2,
Alector-002a (A-002a), was found to express microglia as well as increase pro-
and anti-inflammatory mediators when administered in 5XFAD mice. This finding
was unique in that both pro- and anti-inflammatory responses were expressed
instead of exclusively pro-inflammatory responses, as seen in anti-AB antibody
treatment (15). A-002a was created only to bind and activate TREM2. Binding of
A-002a allows for DAP12 activation by phosphorylation, Syk phosphorylation, and
alterations in gene expression in a downstream effect that ultimately results
in phagocytosis. Activated DAP12 recruits Syk kinases that causes an increase
in intracellular Ca, activation of extracellular signal-regulated kinases
(ERK), and phosphoinositide 3-kinase (PI3K), and translocation of the
transcription factor, nuclear factor of activated T cells (NFAT) (ref). This
stimulated phagocytosis causes a decrease in amyloid deposition and cognitive
improvement when injected chronically into 5XFAD transgenic mice. From this
data, we are able to hypothesize that expression of TREM2 by this antibody will
activate microglia, which express both pro- and anti-inflammatory mediators.

The balance of these opposing mediators will cause a reduction of beta amyloid
deposition as well as tau pathology and degeneration of neurons (Figure 1).

Anti-AB immunotherapy has been investigated as a suggested treatment for AD,
but there have been studies showing adverse effects. There was a significant
amount of microhemorrhages from a chronically administered anti-AB antibody,
which are described as amyloid-related imaging abnormalities that are
hemorrhagic (ARIA-H) (11). Another issue with using Anti-AB immunotherapy as a
treatment is another adverse effect that is of the vasogenic edema nature
(ARIA-E), which describes an increase in extracellular fluid from a disruption
of the blood brain barrier (16). Unlike the immunotherapy against beta amyloid,
we do not believe that the expression of TREM2 and its downstream effects will
induce microhemorrhages (ARIA-H). This is due to the response from A-002a in
that it does not engage matrix metalloproteinases (MMPs), which are thought to
be responsible for the hemorrhages in Anti-AB immunotherapy. Microhemorrhages
have been induced due to MMP activation from pro-inflammatory mediators (19). The
expression of both pro- and anti-inflammatory mediators serves a role in the
lack of disruption of the BBB in TREM2 expression, unlike anti-AB antibodies,
which primarily upregulate pro-inflammatory mediators (Figure 1).

            For this
study, two mouse models are used as well as both sexes investigated.