APOE targeting strategy in Alzheimer’s disease: lessons learned from protective variants,Molecular Neurodegeneration

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APOE targeting strategy in Alzheimer’s disease: lessons learned from protective variants
Molecular Neurodegeneration ( IF 15.1 ) Pub Date : 2022-08-03 , DOI: 10.1186/s13024-022-00556-6
Guojun Bu ₁

Affiliation

The APOE gene is the strongest genetic risk factor for Alzheimer’s disease (AD) with the ε4 allele increasing the risk by 2-4 folds compared to the most common ε3 allele [1]. The high prevalence of APOE4 allele frequency (~ 14% in Caucasian non-demented versus ~ 38% in AD) and carrier frequency (~ 20-30% in Caucasian non-demented versus 50-70% in AD) in AD patients presents a strong rationale to target APOE for AD prevention and therapy [1]. More interestingly, carriers of the APOE2 allele have a significantly reduced risk for AD [2], further attracting interests to target this strong AD risk gene.

The apolipoprotein E (apoE) protein encoded by the APOE gene is a major lipid carrier in both periphery and the brain transporting and distributing lipids across cells and tissues with recognized roles in homeostasis and injury repair [1]. In AD, strong clinical and preclinical evidence suggests that the main pathway by which APOE4 drives AD risk is to promote earlier and more abundant amyloid-β (Aβ) deposition, likely by inhibiting Aβ clearance and accelerating Aβ aggregation and amyloid seeding [1]. Although Aβ plaque is a defining pathological feature of AD, it is not sufficient to cause dementia. Efforts in targeting Aβ has generated mostly disappointing clinical outcomes which is not surprising considering that Aβ deposition occurs up to two decades before the clinical onset and that the amounts of Aβ plaque typically do not correlate with dementia. As such, targeting Aβ might need to be explored as a prevention rather than a treatment strategy. Because Aβ deposition triggers or accelerates additional pathogenic events including microglia-mediated immune response and tau tangle spread, effective strategy targeting Aβ will likely be primary prevention prior to plaque development.

ApoE isoforms also have differential effects on multiple other AD-related pathogenic pathways highlighted by endocytic trafficking, immune response, cerebrovascular integrity, tau-mediated neurodegeneration, and energy metabolism [1, 3], some might be Aβ-independent. Indeed, APOE genotype also has differential effects on age-related cognitive decline and Lewy body dementia parallel to their risk profile for AD. How apoE isoforms that differ at only two amino acids (apoE2: Cys112 and Cys158; apoE3: Cys112 and Arg158; apoE4: Arg112 and Arg158) (Fig. 1) have such profound effects on risk for AD and other age-related dementias has puzzled the field for decades. Recently, an ApoE cascade hypothesis was proposed where it emphasizes the structural and related biochemical differences including lipidation, protein levels, receptor binding, and oligomerization, among the three isoforms as drivers of downstream effects at the cellular and phenotypical levels [4]. As such, targeting the biochemical features of apoE will likely yield greater and broader effects on multiple AD-related pathways.

Although targeting strategies developed against apoE4 or learned from apoE4 are emerging including down-regulation of apoE4 levels [5], the apoE field still struggles with nominating alternative, perhaps more effective ways of targeting apoE in general. Towards this, lessons learned from studying apoE2 has provided significant insights [2]. Despite limited attention to apoE2 compared to apoE4 in preclinical studies, emerging evidence suggests that a major pathway by which apoE2 protects against AD and promotes healthy brain aging is by enhancing lipid efflux and related lipid metabolism. ApoE2 is associated with greater lipidation in CSF and higher apoE protein levels in both periphery and the brain. Interestingly, the higher apoE levels and lower cholesterol in brain parenchyma are associated with better memory performance [6] and longevity [7] in human apoE-targeted replacement mice. ApoE2 is also associated with unique lipidomic and metabolomic profiles in plasma [8, 9]. This knowledge of apoE2 highlights the potential beneficial effects of enhancing lipid efflux and promoting lipid metabolism as a lead strategy to treat AD and related dementia.

In addition to the common variants, recent studies have identified several APOE rare protective variants that offer new insights on apoE properties linked to their protective effects (Fig. 1). Top of the list is the APOE3-Christchurch (R136S) variant where a homozygous carrier with a PSEN1 mutation had a delayed onset of mild cognitive impairment by three decades [10]. Brain imaging studies detected high amyloid load but limited tau pathology and neurodegeneration, suggesting a protective mechanism that is resilient against amyloid. One known effect of the R136S mutation is the reduced binding to the low-density lipoprotein (LDL) receptor and heparan sulfate proteoglycan (HSPG). Interestingly, several pathogenic molecules in AD including Aβ, tau, α-synuclein, and apoE bind to cell surface HSPG which has been implicated in proteinopathy in neurodegenerative diseases by modulating protein trafficking, aggregation, and propagation. How does reduced apoE binding to HSPG lightens the risk to AD is still unclear but given the detrimental effects of HSPG in pathogenic events, it is possible that targeting apoE-HSPG interaction can be beneficial to reducing dementia-related outcomes. One caution for lessons learned with the APOE3-Christchurch variant is that all information to date on APOE3-Christchurch is from study of one individual with incomplete information on neuropathological, biomarker, and other outcomes. Preclinical studies using animal models and cellular models are needed to address specific effects of this variant on neuropathological features (i.e., amyloid plaques and tau tangles), immune response, lipid metabolism, vascular integrity and function, and other AD-related pathways. It is interesting to note that both APOE3-Christchurch and APOE2 homozygosity are associated with Type III hyperlipoproteinemia. Additionally, apoE2 is deficient in binding to the LDL receptor and has the lowest affinity to heparin compared to apoE3 and apoE4. As such, it is templating to speculate that the protective mechanisms of APOE3-Christchurch and APOE2 are likely related in pathways relevant to receptor binding and lipid metabolism.

Another APOE protective variant is APOE3-Jacksonville (V236E) with the mutation localizing in the apoE C-terminal domain, which is best known for apoE lipid-binding function. The protective effect was first reported in 2014 [11] but only recently the underlying mechanism was revealed as reducing apoE self-aggregation [12]. Specifically, the apoE3-Jacksonville mutation reduces the tendency to aggregate both in mammalian cells and when produced in bacteria. More importantly, reduced apoE aggregation is associated with greater ability to promote cholesterol efflux, a process thought to require the apoE monomeric form. ApoE3-Jacksonville is also associated with enhanced lipid-association and when expressed in an amyloid mouse model, reduces amyloid load and related toxicity [12]. These mechanistic insights suggest that reducing apoE self-aggregation can be an alternative apoE targeting strategy to enhance apoE protective effect against AD. Reduced apoE aggregation likely alleviates the detrimental effect of apoE in amyloid seeding and promotes endocytic trafficking of apoE-interacting receptors such as apoE receptor 2 (ApoER2/LRP8), glutamate receptors, insulin receptor, and lipid-efflux transporter ABCA1. More importantly, as intracellular lipid accumulation has been increasingly recognized as a major pathogenic event in aging and AD [13], the potentially enhanced function of apoE in lipid efflux will likely promote repair and healthy brain aging.

More recently, Le Guen et al reported genetic identification of two rare APOE protective variants [14]. In addition to confirming the protective effect of APOE3-Jacksonville, they discovered a new protective variant APOE4-R251G which co-segregates with the APOE4 allele. By analyzing multiple cohorts and combining data for meta-analysis, the genetic data are in general convincing despite the typical difficulties in genetic association studies on rare variants. As with APOE3-Jacksonville, the APOE4-R251G is also localized in the C-terminal domain of apoE (Fig. 1). Specifically, the R251G mutation is located within the lipid-binding region, perhaps just outside the area where apoE initially binds lipid. How this specific mutation is protective against AD risk is not clear, but two possibilities worth exploring. First, the change from a hydrophilic residue to a non-polar residue could enhance lipid binding thus promoting apoE function in lipid metabolism as it relates to brain homeostasis and injury repair. Second, the R251G mutation could potentially change the apoE4 structure such that it either reduces its harmful effects or enhances its physiological functions [1]. Towards this, it is interesting to note that the R251 residue was proposed to form a salt bridge with the Q98 residue as part of apoE domain-domain interaction in a structural study of a mutated apoE3 [15]. Collectively, the APOE3-Jacksonville and APOE4-R251G protective variants offer new clues as to how apoE C-terminal domain impacts AD and related dementias and how knowledge learned from them can guide new apoE-targeting strategies.

Although APOE common variants, APOE2 and APOE4, continue to teach us how apoE-related outcomes contribute to AD pathogenesis, functional rare variants such as APOE3-Christchurch, APOE3-Jacksonville, and APOE4-R251G can provide additional insights. The fact that these rare variants carrying mutations in different regions of apoE offers additional opportunities to explore how structural and related biochemical properties of apoE impact its pathophysiology in aging and AD. Along with the common APOE2 variant, these APOE rare protective variants can teach us how to target apoE as we seek effective ways to prevent and cure AD and other age-related dementias.

Not applicable.

Aβ:: Amyloid-β
AD:: Alzheimer’s disease
ApoE:: Apolipoprotein E
Ch:: Christchurch
HSPG:: Heparan sulfate proteoglycan
Jac:: Jacksonville (Jac)
LDL:: Low-density lipoprotein

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The author thanks Danielle Feathers, Hongmei Li, Lucy Job, Chia-Chen Liu, and Na Zhao for critical reading of the manuscript.

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Molecular Neurodegeneration, Jacksonville, USA
Guojun Bu

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G.B. consults for SciNeuro, has consulted for AbbVie, E-Scape, Eisai, Vida Ventures, Lexeo, and is on the scientific advisory board for Kisbee.

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Bu, G. APOE targeting strategy in Alzheimer’s disease: lessons learned from protective variants. Mol Neurodegeneration 17, 51 (2022). https://doi.org/10.1186/s13024-022-00556-6

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Received: 25 July 2022
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DOI: https://doi.org/10.1186/s13024-022-00556-6

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中文翻译：

阿尔茨海默病中的 APOE 靶向策略：从保护性变异中吸取的教训

APOE基因是阿尔茨海默病 (AD) 最强的遗传风险因素，与最常见的 ε3 等位基因相比，ε4 等位基因使风险增加 2-4 倍 [1] 。AD 患者中APOE4等位基因频率的高患病率（高加索非痴呆患者为 14%，AD 患者为 38%）和携带者频率（高加索非痴呆患者为 20-30%，AD 患者为 50-70%）以APOE为目标进行 AD 预防和治疗的有力理由[1]。更有趣的是，APOE2等位基因的携带者患 AD 的风险显着降低 [2]，进一步吸引了人们关注这种强大的 AD 风险基因。

由APOE基因编码的载脂蛋白 E (apoE) 蛋白是外周和大脑中的主要脂质载体，在细胞和组织之间运输和分布脂质，在体内平衡和损伤修复中具有公认的作用 [1]。在 AD 中，强有力的临床和临床前证据表明APOE4的主要途径驱动 AD 风险的是促进更早和更丰富的淀粉样蛋白-β (Aβ) 沉积，可能通过抑制 Aβ 清除和加速 Aβ 聚集和淀粉样蛋白播种 [1]。尽管 Aβ 斑块是 AD 的一个明确的病理特征，但它不足以引起痴呆。靶向 Aβ 的努力产生的临床结果大多令人失望，考虑到 Aβ 沉积发生在临床发病前长达 20 年，并且 Aβ 斑块的数量通常与痴呆症无关，这并不奇怪。因此，靶向 Aβ 可能需要作为一种预防而非治疗策略进行探索。因为 Aβ 沉积会触发或加速其他致病事件，包括小胶质细胞介导的免疫反应和 tau 缠结扩散，

ApoE 亚型对其他多种 AD 相关的致病途径也有不同的影响，这些途径包括内吞转运、免疫反应、脑血管完整性、tau 介导的神经变性和能量代谢 [1, 3]，有些可能不依赖于 Aβ。确实，APOE基因型对与年龄相关的认知能力下降和路易体痴呆也有不同的影响，这与他们患 AD 的风险相似。仅在两个氨基酸上不同的 apoE 同种型（apoE2：Cys112 和 Cys158；apoE3：Cys112 和 Arg158；apoE4：Arg112 和 Arg158）（图 1）如何对 AD 和其他与年龄相关的痴呆症的风险产生如此深远的影响？领域数十年。最近，提出了 ApoE 级联假说，其中强调了结构和相关的生化差异，包括脂化、蛋白质水平、受体结合和寡聚化，这三种亚型是细胞和表型水平下游效应的驱动因素 [4]。因此，针对 apoE 的生化特征可能会对多种 AD 相关途径产生更大和更广泛的影响。

尽管针对 apoE4 开发或从 apoE4 学习的靶向策略正在出现，包括下调 apoE4 水平 [5]，但 apoE 领域仍然在努力寻找替代的、可能更有效的靶向 apoE 的方法。为此，从研究 apoE2 中吸取的经验教训提供了重要的见解 [2]。尽管在临床前研究中与 apoE4 相比对 apoE2 的关注有限，但新出现的证据表明，apoE2 防止 AD 和促进健康大脑衰老的主要途径是通过增强脂质外流和相关的脂质代谢。ApoE2 与 CSF 中更高的脂质化以及外周和大脑中更高的 apoE 蛋白水平相关。有趣的是，脑实质中较高的 apoE 水平和较低的胆固醇与人类 apoE 靶向替代小鼠的更好的记忆能力 [6] 和寿命 [7] 相关。ApoE2 还与血浆中独特的脂质组学和代谢组学特征相关 [8, 9]。对 apoE2 的了解突出了增强脂质外流和促进脂质代谢作为治疗 AD 和相关痴呆的主要策略的潜在有益作用。

除了常见的变体之外，最近的研究还发现了几种APOE罕见的保护性变体，这些变体提供了关于与其保护作用相关的 apoE 特性的新见解（图 1）。排在首位的是APOE3 -Christchurch (R136S) 变体，其中带有PSEN1的纯合子携带者突变使轻度认知障碍的发病延迟了 30 年 [10]。脑成像研究检测到高淀粉样蛋白负荷，但有限的 tau 病理学和神经变性，表明对淀粉样蛋白具有弹性的保护机制。R136S 突变的一种已知影响是与低密度脂蛋白 (LDL) 受体和硫酸乙酰肝素蛋白聚糖 (HSPG) 的结合减少。有趣的是，AD 中的几种致病分子包括 Aβ、tau、α-突触核蛋白和 apoE 与细胞表面 HSPG 结合，这通过调节蛋白质运输、聚集和传播与神经退行性疾病中的蛋白质病有关。减少 apoE 与 HSPG 的结合如何减轻 AD 的风险仍不清楚，但考虑到 HSPG 在致病事件中的有害影响，靶向apoE-HSPG相互作用可能有助于减少痴呆相关结果。对从APOE3 -Christchurch 变体是迄今为止关于APOE3 -Christchurch 的所有信息均来自对神经病理学、生物标志物和其他结果信息不完整的个体的研究。需要使用动物模型和细胞模型进行临床前研究，以解决这种变体对神经病理学特征（即淀粉样蛋白斑和 tau 缠结）、免疫反应、脂质代谢、血管完整性和功能以及其他 AD 相关途径的特定影响。有趣的是，APOE3 -Christchurch 和APOE2纯合子与 III 型高脂蛋白血症有关。此外，apoE2 缺乏与 LDL 受体的结合，与 apoE3 和 apoE4 相比，apoE2 对肝素的亲和力最低。因此，推测 APOE3-Christchurch 和 APOE2 的保护机制可能与受体结合和脂质代谢相关的途径有关。

另一个APOE保护变体是APOE3-Jacksonville (V236E)，突变定位于 apoE C 末端结构域，以 apoE 脂质结合功能而闻名。保护作用于 2014 年首次报道 [11]，但直到最近才揭示其潜在机制是减少 apoE 自聚集 [12]。具体来说，apoE3-Jacksonville 突变降低了在哺乳动物细胞中和在细菌中产生时聚集的趋势。更重要的是，减少的 apoE 聚集与促进胆固醇流出的能力更强有关，这一过程被认为需要 apoE 单体形式。ApoE3-Jacksonville 还与增强的脂质结合有关，当在淀粉样蛋白小鼠模型中表达时，可降低淀粉样蛋白负荷和相关毒性 [12]。这些机制见解表明，减少 apoE 自聚集可以作为一种替代的 apoE 靶向策略，以增强 apoE 对 AD 的保护作用。减少的 apoE 聚集可能减轻 apoE 在淀粉样蛋白播种中的不利影响，并促进 apoE 相互作用受体如 apoE 受体 2 (ApoER2/LRP8)、谷氨酸受体、胰岛素受体和脂质外排转运蛋白 ABCA1 的内吞转运。更重要的是，随着细胞内脂质积累越来越多地被认为是衰老和 AD 的主要致病事件 [13]，apoE 在脂质流出中的潜在增强功能可能会促进修复和健康的大脑衰老。减少的 apoE 聚集可能减轻 apoE 在淀粉样蛋白播种中的不利影响，并促进 apoE 相互作用受体如 apoE 受体 2 (ApoER2/LRP8)、谷氨酸受体、胰岛素受体和脂质外排转运蛋白 ABCA1 的内吞转运。更重要的是，随着细胞内脂质积累越来越多地被认为是衰老和 AD 的主要致病事件 [13]，apoE 在脂质流出中的潜在增强功能可能会促进修复和健康的大脑衰老。减少的 apoE 聚集可能减轻 apoE 在淀粉样蛋白播种中的不利影响，并促进 apoE 相互作用受体如 apoE 受体 2 (ApoER2/LRP8)、谷氨酸受体、胰岛素受体和脂质外排转运蛋白 ABCA1 的内吞转运。更重要的是，随着细胞内脂质积累越来越被认为是衰老和 AD 的主要致病事件 [13]，apoE 在脂质流出中的潜在增强功能可能会促进修复和健康的大脑衰老。

最近，Le Guen 等人报道了两种罕见的APOE保护性变异的基因鉴定 [14]。除了确认APOE3 -Jacksonville 的保护作用外，他们还发现了一种新的保护性变体APOE4 -R251G，它与APOE4等位基因共分离。通过分析多个队列并结合数据进行荟萃分析，尽管罕见变异的遗传关联研究存在典型的困难，但遗传数据总体上令人信服。与APOE3 -Jacksonville 一样，APOE4-R251G 也位于 apoE 的 C 端结构域（图 1）。具体来说，R251G 突变位于脂质结合区域内，可能就在 apoE 最初结合脂质的区域之外。这种特定突变如何预防 AD 风险尚不清楚，但有两种可能性值得探索。首先，从亲水残基到非极性残基的变化可以增强脂质结合，从而促进脂质代谢中的 apoE 功能，因为它与脑内稳态和损伤修复有关。其次，R251G 突变可能会改变 apoE4 的结构，从而减少其有害影响或增强其生理功能 [1]。对此，有趣的是，R251 残基被提议与 Q98 残基形成盐桥，作为突变 apoE3 结构研究中 apoE 结构域-结构域相互作用的一部分 [15]。总的来说，APOE3 -Jacksonville 和APOE4 -R251G 保护性变体提供了关于 apoE C 末端结构域如何影响 AD 和相关痴呆症以及从中学到的知识如何指导新的 apoE 靶向策略的新线索。

尽管APOE常见变体APOE2和APOE4继续告诉我们 apoE 相关结果如何促成 AD 发病机制，但功能性罕见变体如APOE3 -Christchurch、APOE3 -Jacksonville 和APOE4 -R251G 可以提供额外的见解。这些在 apoE 不同区域携带突变的罕见变体为探索 apoE 的结构和相关生化特性如何影响其在衰老和 AD 中的病理生理学提供了额外的机会。除了常见的APOE2变体，这些APOE罕见的保护性变异可以教会我们如何针对 apoE，因为我们正在寻找预防和治疗 AD 和其他与年龄相关的痴呆症的有效方法。

不适用。

β：: 淀粉样蛋白-β
广告：: 阿尔茨海默氏病
载脂蛋白E：: 载脂蛋白E
频道：: 基督城
HSPG：: 硫酸乙酰肝素蛋白聚糖
杰克：: 杰克逊维尔 (Jac)
低密度脂蛋白：: 低密度脂蛋白

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