Amontree Matthew, Deasy Samantha, Turner R Scott, Conant Katherine
Department of Neuroscience, Georgetown University Medical Center, Washington, DC, United States.
Department of Neurology, Georgetown University Medical Center, Washington, DC, United States.
Front Neurosci. 2023 May 26;17:1188065. doi: 10.3389/fnins.2023.1188065. eCollection 2023.
Alzheimer's Disease (AD) and related dementias are a leading cause of death globally and are predicted to increase in prevalence. Despite this expected increase in the prevalence of AD, we have yet to elucidate the causality of the neurodegeneration observed in AD and we lack effective therapeutics to combat the progressive neuronal loss. Throughout the past 30 years, several non-mutually exclusive hypotheses have arisen to explain the causative pathologies in AD: amyloid cascade, hyper-phosphorylated tau accumulation, cholinergic loss, chronic neuroinflammation, oxidative stress, and mitochondrial and cerebrovascular dysfunction. Published studies in this field have also focused on changes in neuronal extracellular matrix (ECM), which is critical to synaptic formation, function, and stability. Two of the greatest non-modifiable risk factors for development of AD (aside from autosomal dominant familial AD gene mutations) are aging and APOE status, and two of the greatest modifiable risk factors for AD and related dementias are untreated major depressive disorder (MDD) and obesity. Indeed, the risk of developing AD doubles for every 5 years after ≥ 65, and the allele increases AD risk with the greatest risk in homozygous carriers. In this review, we will describe mechanisms by which excess ECM accumulation may contribute to AD pathology and discuss pathological ECM alterations that occur in AD as well as conditions that increase the AD risk. We will discuss the relationship of AD risk factors to chronic central nervous system and peripheral inflammation and detail ECM changes that may follow. In addition, we will discuss recent data our lab has obtained on ECM components and effectors in and expressing murine brain lysates, as well as human cerebrospinal fluid (CSF) samples from and expressing AD individuals. We will describe the principal molecules that function in ECM turnover as well as abnormalities in these molecular systems that have been observed in AD. Finally, we will communicate therapeutic interventions that have the potential to modulate ECM deposition and turnover .
阿尔茨海默病（AD）及相关痴呆症是全球主要的死亡原因之一，预计其患病率还会上升。尽管预计AD患病率会增加，但我们尚未阐明AD中观察到的神经退行性变的因果关系，并且缺乏有效的疗法来对抗进行性神经元丧失。在过去30年中，出现了几种并非相互排斥的假说来解释AD的致病病理：淀粉样蛋白级联反应、过度磷酸化的tau蛋白积累、胆碱能丧失、慢性神经炎症、氧化应激以及线粒体和脑血管功能障碍。该领域已发表的研究也聚焦于神经元细胞外基质（ECM）的变化，而ECM对突触的形成、功能和稳定性至关重要。AD发生（除常染色体显性家族性AD基因突变外）的两个最大的不可改变风险因素是衰老和载脂蛋白E（APOE）状态，而AD及相关痴呆症的两个最大的可改变风险因素是未治疗的重度抑郁症（MDD）和肥胖。事实上，65岁及以上人群每过5年患AD的风险就会加倍，并且ε4等位基因会增加AD风险，纯合子携带者风险最高。在本综述中，我们将描述过量ECM积累可能导致AD病理的机制，并讨论AD中发生的病理性ECM改变以及增加AD风险的情况。我们将讨论AD风险因素与慢性中枢神经系统和外周炎症的关系，并详细说明可能随之出现的ECM变化。此外，我们将讨论我们实验室在表达APP和PS1的小鼠脑裂解物以及来自表达APP和PS1的AD个体的人脑脊液（CSF）样本中获得的关于ECM成分和效应器的最新数据。我们将描述在ECM周转中起作用的主要分子以及在AD中观察到的这些分子系统的异常。最后，我们将介绍有可能调节ECM沉积和周转的治疗干预措施。
