From the Rush Alzheimer's Disease Center (L.Y., Y.W., J.A.S., A.S.B., D.A.B.) and Department of Neurological Sciences (L.Y., Y.W., J.A.S., A.S.B., D.A.B.), Rush University Medical Center, Chicago, IL; Ann Romney Center for Neurologic Diseases (Y.H., R.V.P., T.L.P.), Department of Neurology, Brigham and Women's Hospital, Boston, MA; Harvard Medical School (Y.H., R.V.P., T.L.P.), Boston, MA; Pacific Northwest National Laboratory (V.A.P.), Richland, WA; Department of Pathology (J.A.S.), Rush University Medical Center, Chicago, IL; Department of Biochemistry (N.T.S.), Emory University, Atlanta, GA; and Center for Translational and Computational Neuroimmunology (P.L.D.), Department of Neurology & Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University Medical Center, New York.
Neurology. 2022 Nov 15;99(20):e2264-e2274. doi: 10.1212/WNL.0000000000201120. Epub 2022 Aug 10.
Identifying protein targets that provide cognitive reserve is a strategy to prevent and treat Alzheimer disease and Alzheimer disease related dementias (AD/ADRD). Previous studies using bulk human brain tissue reported 12 proteins associated with cognitive reserve. This study examined whether the same proteins from induced neurons (iNs) are associated with cognitive reserve of their human donors.
Induced pluripotent stem cell (iPSC) lines were generated from cryopreserved peripheral blood mononuclear cells of older adults who were autopsied as part of the Religious Orders Study or Rush Memory and Aging Project. Neurons were induced from iPSCs using a standard neurogenin2 protocol. Tandem mass tag proteomics analyses were conducted on iNs day 21. Cognitive reserve of their human donors was measured as person-specific slopes of cognitive change not accounted for by common neuropathologies.
The 53 human donors died at a mean age of 91 years, all were non-Latino White, and 36 (67.9%) were female. Eighteen were diagnosed with Alzheimer dementia proximate to death, and 34 had pathologic AD diagnosis at autopsy. Approximately 60% of the donors had above-average cognitive reserve such that their cognition declined slower than an average person with comparable burdens of neuropathologies. Eight of the 12 candidate proteins were quantified in iNs proteomics analyses. Higher adenylate kinase 4 (AK4) expression in iNs was associated with lower cognitive reserve, consistent with the previous report for brain AK4 expression.
By replicating cortical protein associations with cognitive reserve in human iNs, these data provide a valuable molecular readout for studying complex clinical phenotypes such as cognitive reserve in a dish.
鉴定具有认知储备能力的蛋白质靶标是预防和治疗阿尔茨海默病和阿尔茨海默病相关痴呆症（AD/ADRD）的一种策略。之前使用人体脑组织的研究报告了与认知储备相关的 12 种蛋白质。本研究检验了诱导神经元（iNs）中的相同蛋白质是否与人类供体的认知储备有关。
从作为宗教秩序研究或拉什记忆与衰老项目一部分进行尸检的老年人大脑冷冻保存的外周血单核细胞中生成诱导多能干细胞（iPSC）系。使用标准神经基因 2 方案从 iPSC 中诱导神经元。对 iNs 第 21 天进行串联质量标签蛋白质组学分析。人类供体的认知储备是通过特定于个体的认知变化斜率来衡量的，该斜率无法用常见的神经病理学来解释。
53 名人类供体的平均死亡年龄为 91 岁，均为非拉丁裔白人，其中 36 名（67.9%）为女性。18 名在接近死亡时被诊断为阿尔茨海默病痴呆症，34 名在尸检时被诊断为病理性 AD。大约 60%的供体具有高于平均水平的认知储备，使得他们的认知下降速度比具有类似神经病理学负担的普通人慢。在 iNs 蛋白质组学分析中定量了 12 种候选蛋白中的 8 种。iNs 中腺嘌呤激酶 4（AK4）的表达较高与认知储备较低有关，这与先前对大脑 AK4 表达的报告一致。
通过在人类 iNs 中复制皮质蛋白与认知储备的关联，这些数据为在体外研究认知储备等复杂临床表型提供了有价值的分子读数。
