Partial FAM19A5 Deficiency in Mice Leads to Disrupted Spine Maturation, Hyperactivity, and an Altered Fear Response

Shahapal, Anu; Park, Sumi; Yoo, Sangjin; Hwang, Jong-Ik; Seong, Jae Young

doi:10.1101/2024.04.29.591582

Cited by 4 publications

(3 citation statements)

References 28 publications

(49 reference statements)

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“…FAM19A5LacZ mice carry a LacZ reporter gene inserted before exon 4 of the FAM19A5 gene. Consequently, these mice are expected to have lower FAM19A5 levels in the brain compared to wild-type mice 12 .…”

Section: Resultsmentioning

confidence: 99%

“…FAM19A5LacZ mice carry a LacZ reporter gene inserted before exon 4 of the FAM19A5 gene. Consequently, these mice are expected to have lower FAM19A5 levels in the brain than wild-type mice [14]. We then crossed FAM19A5LacZ hemizygous mice with APP/PS1 mice to generate WT, APP/PS1 and APP/PS1/FAM19A5 +/LacZ mice.…”

Section: Effect Of Partial Fam19a5 Knockout On App/ps1 Transgenic Micementioning

confidence: 99%

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FAM19A5 Deficiency Mitigates the Aβ Plaque Burden and Improves Cognition in Mouse Models of Alzheimer’s Disease

Park,

Shahapal,

Yoo

et al. 2024

Preprint

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FAM19A5, a novel secretory protein highly expressed in the brain, is potentially associated with the progression of Alzheimer's disease (AD). However, its role in the AD brain remains unclear. Here, we investigated the potential function of FAM19A5 in the context of AD. We generated APP/PS1 mice with partial FAM19A5 deficiency, termed APP/PS1/FAM19A5LacZ+/-. Compared to control APP/PS1 mice, APP/PS1/FAM19A5LacZ+/- mice exhibited significantly lower Aβ plaque density, suggesting that FAM19A5 reduction mitigates Aβ plaque formation. Notably, FAM19A5 partial depletion also prolonged the lifespan of APP/PS1 mice. To further explore the therapeutic potential of FAM19A5 targeting, we developed an anti-FAM19A5 antibody. Administration of this antibody to APP/PS1 mice significantly improved their performance in the novel object recognition test, demonstrating enhanced cognitive function. This effect was reproduced in 5XFAD mice, a model of early-onset AD with rapid Aβ accumulation. Additionally, anti-FAM19A5 antibody treatment in 5XFAD mice led to increased spontaneous alternation behavior in the Y-maze test, indicating improved spatial working memory. These findings suggest that anti-FAM19A5 antibodies may be a promising therapeutic strategy for AD by reducing Aβ plaques and improving cognitive function.

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Section: Resultsmentioning

confidence: 99%

Section: Effect Of Partial Fam19a5 Knockout On App/ps1 Transgenic Micementioning

confidence: 99%

FAM19A5 Deficiency Mitigates the Aβ Plaque Burden and Improves Cognition in Mouse Models of Alzheimer’s Disease

Park,

Shahapal,

Yoo

et al. 2024

Preprint

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“…Tracing the expression pattern of FAM19A5 in FAM19A5-lacZ knock-in mice revealed its presence in neural precursor cells during the early stages of embryonic development, suggesting that it plays a pivotal role in neural growth and circuit establishment 8 . Recent knockout studies have further highlighted the crucial role of FAM19A5 in the later stages of synaptogenesis and pruning processes, potentially in shaping synaptic connectivity and related brain functions 9,10 . Moreover, genome-wide association studies have linked FAM19A5 with various neurological disorders, including Alzheimer's disease (AD), attention deficit hyperactivity disorder, and autism, highlighting its significance in the pathophysiology of these conditions 11,12 .The amino acid sequence of FAM19A5 remains highly conserved across vertebrates, including humans, but the divergence from the FAM19A1-4 family is significant, indicating that FAM19A5 has a distinct function in the brain 13,14 .…”

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confidence: 99%

Inhibition of FAM19A5 restores synaptic loss and improves cognitive function in mouse models of Alzheimer’s disease

Kim,

Yoo,

Kwak

et al. 2023

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Alzheimer’s disease (AD) is characterized by the progressive loss of synapses, leading to cognitive decline. Immunotherapies targeting amyloidosis or tauopathy have shown promise in AD treatment, but additional therapies are needed to inhibit continuous and excessive synaptic loss, which could improve clinical outcomes by modifying the course of the disease. Understanding the mechanisms of synaptic loss is essential for the development of new therapies. Here, we propose an antibody-based immunotherapy targeting FAM19A5, a secretory protein in the brain. We found that FAM19A5 binds to LRRC4B, a post-synaptic adhesion molecule, which disassembles synaptic connections, leading to synapse elimination. FAM19A5 levels increased in association with aging and the progression of tau accumulation. We inhibited FAM19A5 using NS101, an anti-FAM19A5 monoclonal antibody, in mouse models of AD. NS101 preserved synaptic connections despite the presence of amyloid or tau aggregates. Consequently, the number of mature synapses and their function were restored, resulting in improved cognitive performance. In study participants, NS101 was delivered to the human brain across the blood-brain barrier, bound to FAM19A5, and cleared into the peripheral circulation without any toxicity. These findings demonstrate that restoring synapses by inhibiting synaptic elimination can be an effective therapeutic strategy and provide a fundamental basis for modifying AD.One-Sentence SummaryThe antibody NS101 targeting FAM19A5 restores synapse number and function in Alzheimer’s disease, improving cognition.

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Is FAM19A5 an adipokine? Peripheral FAM19A5 in wild-type, FAM19A5 knockout, and LacZ knockin mice

Kwak¹,

Cho²,

Cho³

et al. 2020

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FAM19A5 (also called TAFA5) is a novel secretory protein that is primarily expressed in the brain. However, a recent study reported that FAM19A5 is an adipocyte-derived adipokine that regulates vascular smooth muscle function. Furthermore, genome-wide association study (GWAS) and RNA-seq analyses revealed that the FAM19A5 was associated with a variety of diseases and tumorigenesis in peripheral tissues. We investigated FAM19A5 transcript and protein levels in the FAM19A5 peripheral expression 2 peripheral tissues, including adipose tissues from wild-type, FAM19A5 knock-out, and LacZ knock-in mice. In general, total FAM19A5 transcript levels in the central and peripheral nervous systems were higher than levels in any of the peripheral tissues including adipose tissues. Brain tissues expressed similar levels of the FAM19A5 transcript isoforms 1 and 2, whereas expression in the peripheral tissues predominantly expressed isoform 2. In the peripheral tissues, but not the brain, FAM19A5 protein levels in adipose and reproductive tissues were below detectable limits for analysis by Western blot. Additionally, we found that FAM19A5 protein did not interact with the S1PR2 receptor for G-protein-mediated signal transduction, β-arrestin recruitment, and ligandmediated internalization. Instead, FAM19A5 was internalized into HEK293 cells in an extracellular matrix protein-dependent manner. Taken together, the present study determined basal levels of FAM19A5 transcripts and proteins in peripheral tissues, which provides compelling evidence to further investigate the function of FAM19A5 in peripheral tissues under pathological conditions, including metabolic diseases and/or tumorigenesis.

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Partial FAM19A5 Deficiency in Mice Leads to Disrupted Spine Maturation, Hyperactivity, and an Altered Fear Response

Cited by 4 publications

References 28 publications

FAM19A5 Deficiency Mitigates the Aβ Plaque Burden and Improves Cognition in Mouse Models of Alzheimer’s Disease

FAM19A5 Deficiency Mitigates the Aβ Plaque Burden and Improves Cognition in Mouse Models of Alzheimer’s Disease

Inhibition of FAM19A5 restores synaptic loss and improves cognitive function in mouse models of Alzheimer’s disease

Is FAM19A5 an adipokine? Peripheral FAM19A5 in wild-type, FAM19A5 knockout, and LacZ knockin mice

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