Blood platelet factor 4: the elixir of brain rejuvenation,Molecular Neurodegeneration

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Blood platelet factor 4: the elixir of brain rejuvenation
Molecular Neurodegeneration ( IF 15.1 ) Pub Date : 2024-01-07 , DOI: 10.1186/s13024-023-00681-w
José M. Izquierdo

Aging is invariably associated with some form of cognitive impairment. Three recently published articles in Nature family journals from independent groups reported that the plasma levels of platelet factor four (PF4) are negatively associated with brain aging and neurodegeneration phenotypes and positively associated with cognitive performance, brain rejuvenation and health. These studies identify a humble blood-derived chemokine as a potential elixir of brain youth.

One of the three groups, led by Saul Villeda at the University of California at San Francisco (UCSF), had previously shown that administration of blood plasma from young mice rejuvenated the brains of old mice [1]. When they analyzed how young plasma differed from old plasma, they identified PF4 as the chemokine that transfers the restorative effects of young blood to aging brains [2]. Specifically, PF4 attenuated age-related neuroinflammation by rejuvenating the immune system, rescuing synaptic plasticity and improving hippocampal-dependent learning and memory in a partially CXCR3 chemokine receptor-dependent manner (Fig. 1). A second UCSF team led by Dena Dubal previously showed that klotho, a hormone linked to longevity, could improve cognition when administered to mice [3]; however, because klotho is too large to cross the blood-brain barrier, they concluded that the hormone must act indirectly in the brain. To look for this intermediary, they administered klotho to mice and measured changes in proteins in blood, finding that the levels of several platelet factors, including PF4, increased [4]. The Dubal team also found that systemic administration of PF4 improved neuronal connections in the hippocampus. Nevertheless, klotho effects were still observed in mice lacking PF4, suggesting that PF4 is sufficient but not necessary to recapitulate klotho-mediated cognitive enhancement and that there may be other unidentified platelet factors affecting cognition [4]. In the same vein, there are divergent mechanistic aspects between the observations of Shroer et al. [2], who suggested that the effects of PF4 occur in part through indirect immune mechanisms, and Park et al. [4], who suggested a more direct mechanism of action in the brain. Taken together, these findings may indirectly indicate the coexistence of multiple downstream mechanisms of action involving PF4-related factors, signaling cascades, immune responses, and/or cellular diversity/heterogeneity. Therefore, the mechanistic details and the inter-/intra-relationships between them should be investigated. On the other hand, the same team published a separate study in Nature Aging in July showing that klotho administration improved cognition in aging monkeys [5], but it is unknown whether the improvements involved PF4 (Fig. 1). In the third study, Tara Walker and her team at the University of Queensland (Australia) reported that platelet PF4 levels can be increased by exercise, and that administering PF4 directly into the brains of mice stimulated neurogenesis in the hippocampus, a critical region for memory [6]. They also observed that increasing systemic PF4 levels ameliorated age-related cognitive and regenerative impairment in a hippocampal neurogenesis-dependent manner, leading them to conclude that platelets play a major role in the rejuvenation of the aging brain (hippocampal learning and memory) associated with physical exercise during physiological aging. Collectively, the three studies show that PF4 improves cognition in aged mice [2, 4, 6] (Fig. 1).

A major limitation of these types of study is that few observations in mice translate into safe and effective therapies in humans. However, PF4 levels were found to be elevated in both young humans and mice compared with aged counterparts [2] and administration of human PF4 also improved cognition in mice [6]. Several “treatments” for brain aging are already available, such as physical exercise and calorie restriction, but they are often not an option for those most in need. Indeed, the Walker group demonstrated that platelets release PF4 into circulation after exercise [4], but many people with health conditions or advanced age are unable to exercise, so a pharmacological intervention could fill this gap. For example, platelets could be used to promote neurogenesis and counteract age-related cognitive decline [6]. Although more research is needed to understand how these activities rejuvenate the brain and to identify molecules that mimic their effects, it is possible that PF4-based treatments will be tested in clinical trials in the coming years. Future studies will also need to determine exactly how PF4 works in the body and brain, and whether it should ultimately form part of a therapeutic cocktail. These results might herald a new generation of drugs to dampen age-associated inflammatory and immunosenescent cellular phenotypes, such as taurine, metformin, rapamycin, NAD + precursors, sirtuin activators and antioxidants [7] (Fig. 1).

Platelets are principally known for their role in blood clotting and wound healing, and release platelet factors into the blood. The chemokine PF4 (also called anti-heparin factor or CXCL4) is found in the alpha granules of platelets and has a high affinity for heparin, and typically forms complexes with glycoproteins, such as protein C. In addition to coordinating the movement of leukocytes in inflammatory situations, chemokines are involved in myriad physiological and pathological processes including immune system development; immune surveillance, memory, response and regulation; inflammation; embryogenesis, angiogenesis and organogenesis; nervous system development and function; germ cell migration; cancer development and metastasis [6]. In this regard, the administration of PF4 may cause undesirable side effects. The most common complication of heparin treatment in surgical patients is bleeding, but the most dangerous complication is the development of heparin-induced thrombocytopenia (HIT) [8, 9], and all patients treated with heparin of any type and at any dose are at risk of HIT due to the formation of antibodies against the heparin-PF4 complex, which secondarily activates platelets and coagulation and ultimately leading to increased thrombin generation. The main manifestation is a 50% decrease in platelet count from baseline, and/or thrombotic complications occurring 5–14 days after initiation of heparin treatment [9]. This rare medical condition is also observed in a number of patients receiving the Oxford/AstraZeneca ChAdOx1-S vaccine against COVID-19 [8, 9]. Accordingly, the direct use of PF4 may not be free of risks a priori, such as those associated with the pathogenesis of different diseases including those related to infections (sepsis and viral infections), to tumors, as well as inflammatory processes, autoimmunity and cardiovascular, hepatic and renal diseases [6]. Therefore a deeper understanding of the molecular-mechanistic features of PF4 and its regulatory nodes during blood coagulation is necessary, which should occur hand-in-hand with the development of mimetic drugs to emulate the function and biological activity of this molecule in the absence of complications, favoring the maintenance and/or recovery of compromised brain capacity during aging, as well as during the development of neurological pathologies, dementias and even age-associated muscular dysfunction.

In summary, while PF4 may hold promise, it is perhaps only a small piece of a larger puzzle. For example, Katsimpardi et al. identified GDF11, a protein with comparable restorative effects that are associated with caloric restriction in aged mice [10]. The precise role played by these proteins remains unclear; however, if the present results in mice are reproduced in humans, it may be possible to reverse the effects of brain aging with a “brain rejuvenation elixir” found within the platelets of our blood. The explanation of why physical exercise, the longevity hormone “klotho” and blood transfusion from “young” individuals can induce cognitive improvement is linked to the action of a common factor––the secretion of PF4. The three-way carom suggests that the “holy grail” of brain rejuvenation might lie in understanding the role of PF4 in neuronal plasticity and organ homeostasis.

Villeda SA, Plambeck KE, Middeldorp J, Castellano JM, Mosher KI, Luo J, et al. Young blood reverses age-related impairments in cognitive function and synaptic plasticity in mice. Nat Med. 2014;20(6):659–63.
Article CAS PubMed PubMed Central Google Scholar
Schroer AB, Ventura PB, Sucharov J, Misra R, Kirsten Chui MK, Bieri G, et al. Platelet factors attenuate inflammation and rescue cognition in aging. Nature. 2023;620(7976):1071–79.
Article CAS PubMed PubMed Central Google Scholar
Dubal DB, Yokoyama JS, Zhu L, Broestl L, Worden K, Wang D, et al. Life extension factor klotho enhances cognition. Cell Rep. 2014;7(4):1065–76.
Article CAS PubMed PubMed Central Google Scholar
Park C, Hahn O, Gupta S, Moreno AJ, Marino F, Kedir B, et al. Platelet factors are induced by longevity factor klotho and enhance cognition in young and aging mice. Nat Aging. 2023;3(9):1067–78.
Article PubMed PubMed Central Google Scholar
Castner SA, Gupta S, Wang D, Moreno AJ, Park C, Chen C, et al. Longevity factor klotho enhances cognition in aged nonhuman primates Nat. Aging. 2023;3(8):931–7.
PubMed Google Scholar
Leiter O, Brici D, Fletcher SJ, Yong XLH, Widagdo J, Matigian N, et al. Platelet-derived exerkine CXCL4/platelet factor 4 rejuvenates hippocampal neurogenesis and restores cognitive function in aged mice. Nat Commun. 2023;14(1):4375.
Article CAS PubMed PubMed Central Google Scholar
Tyagi T, Jain K, Gu SX, Qiu M, Gu VW, Melchinger H, et al. A guide to molecular and functional investigations of platelets to bridge basic and clinical sciences. Nat Cardiovasc Res. 2022;1(3):223–37.
Article PubMed PubMed Central Google Scholar
Greinacher A, Thiele T, Warkentin TE, Weisser K, Kyrle PA, Eichinger S. Thrombotic thrombocytopenia after ChAdOx1 nCov-19 vaccination. N Engl J Med. 2021;384(22):2092–101.
Article CAS PubMed Google Scholar
Schultz HH, Sørvoll IH, Michelsen AE, Munthe LA, Lund-Johansen F, Ahlen MT, et al. Thrombosis and thrombocytopenia after ChAdOx1 nCoV-19 vaccination. N Engl J Med. 2021;384(22):2124–30.
Article CAS PubMed Google Scholar
Katsimpardi L, Kuperwasser N, Camus C, Moigneu C, Chiche A, Tolle V, et al. Systemic GDF11 stimulates the secretion of adiponectin and induces a calorie restriction-like phenotype in aged mice. Aging Cell. 2020;19(1):e13038.
Article CAS PubMed Google Scholar

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Research in the author’s laboratory is supported by the Ministry of Science and Innovation and the Spanish Research Agency through FEDER funds (PID2021-1261520B-100) (MICINN/AEI/FEDER, EU). CBMSO receives an institutional grant from the Fundación Ramón Areces, Spain.

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Centro de Biología Molecular Severo Ochoa. Consejo Superior de Investigaciones Científicas, Universidad Autónoma de Madrid (CSIC/UAM), C/ Nicolás Cabrera 1, Campus de Cantoblanco, Madrid, 28049, Spain
José M. Izquierdo

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Correspondence to José M. Izquierdo.

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Izquierdo, J.M. Blood platelet factor 4: the elixir of brain rejuvenation. Mol Neurodegeneration 19, 3 (2024). https://doi.org/10.1186/s13024-023-00681-w

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Received: 18 September 2023
Accepted: 13 November 2023
Published: 07 January 2024
DOI: https://doi.org/10.1186/s13024-023-00681-w

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Keywords

Platelet factor 4
Neuroinflammation
Brain rejuvenation

中文翻译：

血小板因子4：大脑复兴的灵丹妙药

衰老总是与某种形式的认知障碍有关。最近在《自然》家族期刊上发表的来自独立团体的三篇文章报告称，血小板四因子 (PF4) 的血浆水平与大脑衰老和神经退行性表型呈负相关，与认知能力、大脑年轻化和健康呈正相关。这些研究发现一种不起眼的血液趋化因子是大脑年轻的潜在灵丹妙药。

由加州大学旧金山分校 (UCSF) 的 Saul Villeda 领导的三个研究小组之一此前曾表明，注射年轻小鼠的血浆可以使年老小鼠的大脑恢复活力 [1]。当他们分析年轻血浆与老年血浆的差异时，他们发现 PF4 是将年轻血液的恢复作用转移到衰老大脑的趋化因子 [2]。具体而言，PF4 通过恢复免疫系统活力、挽救突触可塑性并以部分 CXCR3 趋化因子受体依赖性方式改善海马依赖性学习和记忆来减轻与年龄相关的神经炎症（图 1）。由 Dena Dubal 领导的加州大学旧金山分校的第二个团队此前表明，klotho（一种与长寿相关的激素）给予小鼠后可以改善认知能力 [3]；然而，由于 klotho 太大而无法穿过血脑屏障，因此他们得出结论，该激素必须间接作用于大脑。为了寻找这种中介，他们给小鼠注射了 klotho 并测量了血液中蛋白质的变化，发现包括 PF4 在内的几种血小板因子的水平增加了 [4]。Dubal 团队还发现，全身施用 PF4 可以改善海马体的神经元连接。尽管如此，在缺乏 PF4 的小鼠中仍然观察到了 klotho 效应，这表明 PF4 足以但不是重演 klotho 介导的认知增强所必需的，并且可能存在其他未识别的血小板因子影响认知[4]。同样，Shroer 等人的观察之间也存在不同的机制方面。[2]，他认为 PF4 的作用部分是通过间接免疫机制发生的，Park 等人。[4]，他提出了大脑中更直接的作用机制。总而言之，这些发现可能间接表明涉及 PF4 相关因子、信号级联、免疫反应和/或细胞多样性/异质性的多种下游作用机制的共存。因此，应该研究其机制细节以及它们之间的相互/内部关系。另一方面，同一团队在《自然衰老》杂志上发表了一项单独的研究7 月份的研究表明，klotho 给药可改善老年猴子的认知能力 [5]，但尚不清楚这种改善是否与 PF4 相关（图 1）。在第三项研究中，澳大利亚昆士兰大学的 Tara Walker 和她的团队报告称，运动可以增加血小板 PF4 水平，并且将 PF4 直接注射到小鼠大脑中可以刺激海马体（记忆的关键区域）的神经发生。 [6]。他们还观察到，增加全身 PF4 水平可以以海马神经发生依赖性方式改善与年龄相关的认知和再生障碍，从而得出结论，血小板在与身体相关的衰老大脑（海马学习和记忆）的恢复中发挥着重要作用。生理衰老过程中的锻炼。总的来说，三项研究表明 PF4 可以改善老年小鼠的认知能力 [2,4,6]（图 1）。

这类研究的一个主要限制是，在小鼠中的观察结果很少转化为对人类的安全有效的治疗。然而，与老年小鼠相比，年轻人类和小鼠的 PF4 水平被发现升高 [2]，并且给予人类 PF4 还可以改善小鼠的认知能力 [6]。目前已经有几种针对大脑衰老的“疗法”，例如体育锻炼和热量限制，但对于那些最需要的人来说，它们往往不是一种选择。事实上，Walker 小组证明，运动后血小板会释放 PF4 进入循环系统 [4]，但许多健康状况不佳或年事已高的人无法运动，因此药物干预可以填补这一空白。例如，血小板可用于促进神经发生并抵消与年龄相关的认知能力下降[6]。尽管需要更多的研究来了解这些活动如何使大脑恢复活力并识别模拟其作用的分子，但基于 PF4 的治疗方法有可能在未来几年在临床试验中进行测试。未来的研究还需要确定 PF4 在身体和大脑中的确切作用，以及它是否最终应该成为治疗鸡尾酒的一部分。这些结果可能预示着新一代药物可以抑制与年龄相关的炎症和免疫衰老细胞表型，例如牛磺酸、二甲双胍、雷帕霉素、NAD+前体、sirtuin激活剂和抗氧化剂[7]（图1）。

血小板主要因其在血液凝固和伤口愈合中的作用以及将血小板因子释放到血液中而闻名。趋化因子 PF4（也称为抗肝素因子或 CXCL4）存在于血小板的 α 颗粒中，对肝素具有高亲和力，通常与糖蛋白（例如蛋白 C）形成复合物。在炎症情况下，趋化因子参与多种生理和病理过程，包括免疫系统的发育；免疫监视、记忆、反应和调节；炎; 胚胎发生、血管发生和器官发生；神经系统的发育和功能；生殖细胞迁移；癌症的发生和转移[6]。在这方面，PF4的施用可能会引起不期望的副作用。手术患者肝素治疗最常见的并发症是出血，但最危险的并发症是发生肝素诱导的血小板减少症 (HIT) [8, 9]，所有接受任何类型和任何剂量肝素治疗的患者均处于由于形成针对肝素-PF4复合物的抗体，该复合物继发激活血小板和凝血，最终导致凝血酶生成增加，因此存在 HIT 风险。主要表现是血小板计数较基线下降50%，和/或开始肝素治疗后5-14天发生血栓并发症[9]。在许多接受牛津/阿斯利康 ChAdOx1-S COVID-19 疫苗的患者中也观察到这种罕见的疾病 [8, 9]。因此，直接使用 PF4 可能存在先验风险，例如与不同疾病发病机制相关的风险，包括与感染（脓毒症和病毒感染）、肿瘤以及炎症过程、自身免疫和心血管相关的风险、肝肾疾病[6]。因此，有必要更深入地了解 PF4 的分子机制特征及其在凝血过程中的调节节点，这应该与模拟药物的开发同时进行，以在缺乏条件的情况下模拟该分子的功能和生物活性。并发症，有利于在衰老过程中以及神经病理学、痴呆症甚至与年龄相关的肌肉功能障碍的发展过程中受损的大脑容量的维持和/或恢复。

总而言之，虽然 PF4 可能有希望，但它可能只是一个更大难题的一小部分。例如，Katsimpardi 等人。鉴定出 GDF11，一种具有类似恢复作用的蛋白质，与老年小鼠的热量限制有关 [10]。这些蛋白质发挥的确切作用尚不清楚。然而，如果在小鼠身上得到的结果能够在人类身上重现，那么就有可能利用我们血液中血小板中发现的“大脑再生灵丹妙药”来逆转大脑衰老的影响。为什么体育锻炼、长寿激素“klotho”和“年轻”个体的输血可以改善认知能力，这与一个共同因素——PF4 分泌的作用有关。三向卡罗姆表明，大脑复兴的“圣杯”可能在于了解 PF4 在神经元可塑性和器官稳态中的作用。

Villeda SA、Plambeck KE、Middeldorp J、Castellano JM、Mosher KI、Luo J 等。年轻的血液可以逆转小鼠认知功能和突触可塑性与年龄相关的损伤。纳特医学。2014；20(6):659–63。
文章 CAS PubMed PubMed Central Google Scholar
Schroer AB、Ventura PB、Sucharov J、Misra R、Kirsten Chui MK、Bieri G 等。血小板因子可减轻炎症并挽救衰老过程中的认知能力。自然。2023；620(7976):1071–79。
文章 CAS PubMed PubMed Central Google Scholar
Dubal DB，Yokoyama JS，Zhu L，Broestl L，Worden K，Wang D，等。寿命延长因子 klotho 可增强认知能力。细胞报告，2014 年；7(4)：1065–76。
文章 CAS PubMed PubMed Central Google Scholar
Park C、Hahn O、Gupta S、Moreno AJ、Marino F、Kedir B 等。血小板因子由长寿因子 klotho 诱导，可增强年轻和衰老小鼠的认知能力。纳特老化。2023；3(9)：1067–78。
文章 PubMed PubMed Central Google Scholar
Castner SA、Gupta S、Wang D、Moreno AJ、Park C、Chen C 等。长寿因子 klotho 可增强老年非人灵长类动物的认知能力 Nat。老化。2023；3(8)：931–7。
考研谷歌学术
Leiter O、Brici D、Fletcher SJ、Yong XLH、Widagdo J、Matigian N 等。血小板衍生的运动因子 CXCL4/血小板因子 4 可恢复老年小鼠海马神经发生并恢复认知功能。纳特·康姆. 2023；14(1):4375。
文章 CAS PubMed PubMed Central Google Scholar
Tyagi T、Jain K、Gu SX、Qiu M、Gu VW、Melchinger H 等。血小板分子和功能研究指南，以连接基础科学和临床科学。纳特心血管研究中心。2022；1(3)：223–37。
文章 PubMed PubMed Central Google Scholar
Greinacher A、Thiele T、Warkentin TE、Weisser K、Kyrle PA、Eichinger S. ChAdOx1 nCov-19 疫苗接种后血栓性血小板减少症。N 英格兰医学杂志。2021；384(22):2092–101。
文章 CAS PubMed 谷歌学术
Schultz HH、Sørvoll IH、Michelsen AE、Munthe LA、Lund-Johansen F、Ahlen MT 等。ChAdOx1 nCoV-19 疫苗接种后血栓形成和血小板减少。N 英格兰医学杂志。2021；384(22):2124–30。
文章 CAS PubMed 谷歌学术
Katsimpardi L、Kuperwasser N、Camus C、Moigneu C、Chiche A、Tolle V 等。全身性 GDF11 刺激脂联素的分泌，并在老年小鼠中诱导热量限制样表型。老化细胞。2020；19(1)：e13038。
文章 CAS PubMed 谷歌学术

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作者实验室的研究得到了科学与创新部和西班牙研究机构通过 FEDER 基金 (PID2021-1261520B-100) (MICINN/AEI/FEDER, EU) 的支持。CBMSO 获得西班牙 Ramón Areces 基金会的机构资助。

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