Department of Public Health/Geriatrics, Uppsala University Hospital, Uppsala University, Box 609, SE-751 25, Uppsala, Sweden.
Acta Neuropathol Commun. 2013 Sep 10;1:60. doi: 10.1186/2051-5960-1-60.
The Arctic mutation (p.E693G/p.E22G)fs within the β-amyloid (Aβ) region of the β-amyloid precursor protein gene causes an autosomal dominant disease with clinical picture of typical Alzheimer's disease. Here we report the special character of Arctic AD neuropathology in four deceased patients.
Aβ deposition in the brains was wide-spread (Thal phase 5) and profuse. Virtually all parenchymal deposits were composed of non-fibrillar, Congo red negative Aβ aggregates. Congo red only stained angiopathic vessels. Mass spectrometric analyses showed that Aβ deposits contained variably truncated and modified wild type and mutated Aβ species. In three of four Arctic AD brains, most cerebral cortical plaques appeared targetoid with centres containing C-terminally (beyond aa 40) and variably N-terminally truncated Aβ surrounded by coronas immunopositive for Aβx-42. In the fourth patient plaque centres contained almost no Aβ making the plaques ring-shaped. The architectural pattern of plaques also varied between different anatomic regions. Tau pathology corresponded to Braak stage VI, and appeared mainly as delicate neuropil threads (NT) enriched within Aβ plaques. Dystrophic neurites were scarce, while neurofibrillary tangles were relatively common. Neuronal perikarya within the Aβ plaques appeared relatively intact.
In Arctic AD brain differentially truncated abundant Aβ is deposited in plaques of variable numbers and shapes in different regions of the brain (including exceptional targetoid plaques in neocortex). The extracellular non-fibrillar Aβ does not seem to cause overt damage to adjacent neurons or to induce formation of neurofibrillary tangles, supporting the view that intracellular Aβ oligomers are more neurotoxic than extracellular Aβ deposits. However, the enrichment of NTs within plaques suggests some degree of intra-plaque axonal damage including accumulation of hp-tau, which may impair axoplasmic transport, and thereby contribute to synaptic loss. Finally, similarly as the cotton wool plaques in AD resulting from exon 9 deletion in the presenilin-1 gene, the Arctic plaques induced only modest glial and inflammatory tissue reaction.
β-淀粉样前体蛋白基因β-淀粉样（Aβ）区域内的 Arctic 突变（p.E693G/p.E22G）导致常染色体显性疾病，其临床表现为典型的阿尔茨海默病。在此，我们报告了 4 名已故患者的 Arctic AD 神经病理学的特殊特征。
大脑中的 Aβ 沉积广泛（Thal 阶段 5）且丰富。实际上，所有实质沉积物均由非纤维状、刚果红阴性 Aβ 聚集体组成。刚果红仅染色血管病。质谱分析表明，Aβ 沉积物中含有不同程度截断和修饰的野生型和突变型 Aβ 物质。在 4 名 Arctic AD 患者中有 3 名，大多数大脑皮质斑块呈靶样，中心包含 C 端（aa40 以后）和可变 N 端截断的 Aβ，周围有 Aβx-42 免疫阳性的冠状物。在第 4 名患者中，斑块中心几乎不含 Aβ，使斑块呈环形。斑块的结构模式也在不同解剖区域之间有所不同。tau 病理学与 Braak 阶段 VI 相对应，主要表现为富含 Aβ 斑块内的精细神经原纤维丝（NT）。树突状神经突起稀少，而神经原纤维缠结相对常见。Aβ 斑块内的神经元胞体相对完整。
在 Arctic AD 大脑中，不同程度截断的丰富 Aβ 沉积在大脑不同区域的斑块中（包括新皮质中异常的靶样斑块）。细胞外非纤维状 Aβ似乎不会对邻近神经元造成明显损伤，也不会诱导神经原纤维缠结形成，这支持了细胞内 Aβ 寡聚物比细胞外 Aβ 沉积更具神经毒性的观点。然而，NT 在斑块内的富集表明斑块内轴突受到一定程度的损伤，包括 hp-tau 的积累，这可能会损害轴突质运输，从而导致突触丢失。最后，与 presenilin-1 基因外显子 9 缺失导致的 AD 中的棉絮状斑块类似，Arctic 斑块仅引起适度的神经胶质和炎症组织反应。
