Faculté de pharmacie, Université Laval, Quebec G1V 0A6, Quebec, Canada.
Axe Neurosciences, Centre de recherche du CHU de Québec-Université Laval, Quebec G1V 4G2, Quebec, Canada.
J Neurosci. 2023 Jun 28;43(26):4941-4954. doi: 10.1523/JNEUROSCI.1945-22.2023. Epub 2023 May 30.
Synaptic loss is intrinsically linked to Alzheimer's disease (AD) neuropathology and symptoms, but its direct impact on clinical symptoms remains elusive. The postsynaptic protein Shank3 (SH3 and multiple ankyrin repeat domains) is of particular interest, as the loss of a single allele of the gene is sufficient to cause profound cognitive symptoms in children. We thus sought to determine whether a SHANK3 deficiency could contribute to the emergence or worsening of AD symptoms and neuropathology. We first found a 30%-50% postmortem loss of SHANK3a associated with cognitive decline in the parietal cortex of individuals with AD. To further probe the role of SHANK3 in AD, we crossed male and female 3xTg-AD mice modelling Aβ and tau pathologies with -deficient mice (Shank3). We observed synergistic deleterious effects of Shank3a deficiency and AD neuropathology on object recognition memory at 9, 12, and 18 months of age and on anxious behavior at 9 and 12 months of age in hemizygous Shank3-3xTg-AD mice. In addition to the expected 50% loss of Shank3a, levels of other synaptic proteins, such as PSD-95, drebrin, and homer1, remained unchanged in the parietotemporal cortex of hemizygous Shank3 animals. However, Shank3a deficiency increased the levels of soluble Aβ and human tau at 18 months of age compared with 3xTg-AD mice with normal Shank3 expression. The results of this study in human brain samples and in transgenic mice are consistent with the hypothesis that Shank3 deficiency makes a key contribution to cognitive impairment in AD. Although the loss of several synaptic proteins has been described in Alzheimer's disease (AD), it remains unclear whether their reduction contributes to clinical symptoms. The results of this study in human samples show lower levels of SHANK3a in AD brain, correlating with cognitive decline. Data gathered in a novel transgenic mouse suggest that Shank3a deficiency synergizes with AD neuropathology to induce cognitive impairment, consistent with a causal role in AD. Therefore, treatment aiming at preserving Shank3 in the aging brain may be beneficial to prevent AD.
突触丧失与阿尔茨海默病（AD）的神经病理学和症状密切相关，但它对临床症状的直接影响仍不清楚。突触后蛋白 Shank3（SH3 和多个锚蛋白重复结构域）特别引人注目，因为该基因的单个等位基因缺失足以导致儿童出现严重的认知症状。因此，我们试图确定 Shank3 缺乏是否会导致 AD 症状和神经病理学的出现或恶化。我们首先发现 AD 患者顶叶皮层的 SHANK3a 存在 30%-50%的死后丢失，与认知能力下降有关。为了进一步研究 SHANK3 在 AD 中的作用，我们将携带 Aβ和 tau 病理学的雄性和雌性 3xTg-AD 小鼠与 Shank3 缺陷（Shank3）小鼠进行杂交。我们观察到 Shank3a 缺乏和 AD 神经病理学在 9、12 和 18 个月大的半合子 Shank3-3xTg-AD 小鼠的物体识别记忆以及 9 和 12 个月大的焦虑行为上具有协同的有害影响。除了预期的 Shank3a 丢失 50%外，半合子 Shank3 动物顶颞叶皮层中的其他突触蛋白（如 PSD-95、drebrin 和 homer1）的水平保持不变。然而，与表达正常 Shank3 的 3xTg-AD 小鼠相比，Shank3a 缺乏会增加 18 个月大时可溶性 Aβ和人 tau 的水平。本研究在人类脑组织样本和转基因小鼠中的结果与 Shank3 缺乏对 AD 认知障碍有重要贡献的假说一致。虽然在阿尔茨海默病（AD）中已经描述了几种突触蛋白的丢失，但尚不清楚其减少是否有助于临床症状。本研究在人类样本中的结果显示 AD 大脑中的 SHANK3a 水平较低，与认知能力下降相关。在一种新的转基因小鼠中收集的数据表明，Shank3a 缺乏与 AD 神经病理学协同作用诱导认知障碍，这与 AD 中的因果关系一致。因此，旨在保护衰老大脑中 Shank3 的治疗方法可能有益于预防 AD。
