Ravasia Kashif, Hirsch-Reinshagen Veronica
School of Medicine, University of British Columbia, Vancouver, Canada.
Division of Neuropathology, Vancouver General Hospital and University of British Columbia, Vancouver, Canada.
Free Neuropathol. 2025 Apr 9;6:11. doi: 10.17879/freeneuropathology-2025-5812. eCollection 2025.
The three main types of frontotemporal lobar degeneration (FTLD) are characterized by the accumulation of abnormal proteins, namely tau, TDP-43 and FUS. The distribution of these proteins within different human brain regions is well known, as is the range of morphological variability of the cellular inclusions they form. Compared to the extensive knowledge that exists about distinct protein aggregates in FTLD, surprisingly little is known about the specific cell (sub)types that these inclusions affect. Even less is known about disease-specific abnormalities other than protein inclusions in affected and unaffected areas. These are non-trivial knowledge gaps. First, knowing which cell subtypes are vulnerable or resilient to the development of pathological protein inclusions is crucial to understand the cellular disease mechanisms. Second, mounting evidence suggests that non-cell autonomous mechanisms may play important roles in neurodegenerative conditions. For example, astrocytic tau pathology is associated with synaptic loss in corticobasal degeneration but not in progressive supranuclear palsy. Furthermore, changes that are more difficult and time-consuming to quantify, for example loss of a specific neuronal subtype that does not develop pathological inclusions, remain virtually unexplored and their relevance for disease progression are unknown. This scoping review is an attempt to collate all histological evidence from human studies that address the question of cell-specific vulnerability in the most common FTLD subtypes. By taking a systematic approach including various brain cell types such as neurons and their subtypes as well as astrocytes, microglia and oligodendrocytes and the entire central nervous system with its affected and unaffected regions, this review summarizes the current status in the field and highlights important knowledge gaps.
额颞叶变性（FTLD）的三种主要类型的特征是异常蛋白质的积累，即tau蛋白、TDP-43和FUS。这些蛋白质在不同人脑区域的分布是众所周知的，它们形成的细胞内含物的形态变异范围也是如此。与FTLD中关于不同蛋白质聚集体的广泛知识相比，令人惊讶的是，对于这些内含物所影响的特定细胞（亚）类型知之甚少。对于受影响和未受影响区域中除蛋白质内含物之外的疾病特异性异常了解得更少。这些都是重要的知识空白。首先，了解哪些细胞亚类型对病理性蛋白质内含物的形成敏感或有抵抗力，对于理解细胞疾病机制至关重要。其次，越来越多的证据表明，非细胞自主机制可能在神经退行性疾病中起重要作用。例如，星形细胞tau病理与皮质基底节变性中的突触丧失有关，但与进行性核上性麻痹无关。此外，更难以量化且耗时的变化，例如未形成病理性内含物的特定神经元亚类型的丧失，实际上仍未得到探索，其与疾病进展的相关性也未知。本综述旨在整理来自人体研究的所有组织学证据，这些证据涉及最常见的FTLD亚型中细胞特异性易感性的问题。通过采用系统的方法，包括各种脑细胞类型，如神经元及其亚型，以及星形胶质细胞、小胶质细胞和少突胶质细胞，以及整个中枢神经系统及其受影响和未受影响的区域，本综述总结了该领域的现状，并突出了重要的知识空白。
