Institute of Neuropathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
Brain Pathol. 2011 Jul;21(4):452-63. doi: 10.1111/j.1750-3639.2010.00469.x. Epub 2011 Jan 27.
Early-onset familial Alzheimer's disease (AD) caused by presenilin-1 mutation E280A (PS1-E280A) presents wide clinical and neuropathological variabilities. We characterized clinically and neuropathologically PS1-E280A focusing in cerebellar involvement and compared it with early-onset sporadic Alzheimer's disease (EOSAD). Twelve E280A brains and 12 matched EOSAD brains were analyzed for beta-amyloid and hyperphosphorylated tau (pTau) morphology, beta-amyloid subspecies 1-40, 1-42 levels, pTau levels, and expression of stress kinases in frontal cortex and cerebellum. The data were correlated to clinical and genetic findings. We observed higher beta-amyloid load, beta-amyloid 1-42 and pTau concentrations in frontal cortex of PS1-E280A compared with EOSAD. High beta-amyloid load was found in the cerebellum of PS1-E280A and EOSAD patients. In PS1-E280A, beta-amyloid localized to the molecular and Purkinje cell layers, whereas EOSAD showed them in Purkinje and granular cell layers. Surprisingly, 11 out of 12 PS1-E280A patients showed deposition of pTau in the cerebellum. Also, seven out of 12 PS1-E280A patients presented cerebellar ataxia. We conclude that deposition of beta-amyloid in the cerebellum is prominent in early-onset AD irrespective of genetic or sporadic origin. The presence of pTau in cerebellum in PS1-E280A underscores the relevance of cerebellar involvement in AD and might be correlated to clinical phenotype.
早发性家族性阿尔茨海默病（AD）由早老素-1 突变 E280A（PS1-E280A）引起，具有广泛的临床和神经病理学变异性。我们重点研究了 PS1-E280A 的临床和神经病理学特征，包括小脑受累情况，并将其与早发性散发性 AD（EOSAD）进行了比较。分析了 12 例 PS1-E280A 脑和 12 例匹配的 EOSAD 脑，以研究β-淀粉样蛋白和磷酸化 tau（pTau）形态、β-淀粉样蛋白亚型 1-40、1-42 水平、pTau 水平以及应激激酶在额叶皮质和小脑的表达。将这些数据与临床和遗传发现相关联。我们观察到 PS1-E280A 额叶皮质中的β-淀粉样蛋白负荷、β-淀粉样蛋白 1-42 和 pTau 浓度高于 EOSAD。PS1-E280A 和 EOSAD 患者的小脑也存在高β-淀粉样蛋白负荷。在 PS1-E280A 中，β-淀粉样蛋白定位于分子和浦肯野细胞层，而 EOSAD 则在浦肯野和颗粒细胞层显示。令人惊讶的是，12 例 PS1-E280A 患者中有 11 例小脑出现 pTau 沉积。此外，12 例 PS1-E280A 患者中有 7 例出现小脑共济失调。我们得出结论，无论遗传或散发性起源，β-淀粉样蛋白在小脑的沉积在早发性 AD 中都很明显。PS1-E280A 小脑 pTau 的存在强调了小脑受累在 AD 中的重要性，并且可能与临床表型相关。
