Linking aβ42-induced hyperexcitability to neurodegeneration, learning and motor deficits, and a shorter lifespan in an Alzheimer's model.
Linking aβ42-induced hyperexcitability to neurodegeneration, learning and motor deficits, and a shorter lifespan in an Alzheimer's model.
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DOI：
10.1371/journal.pgen.1005025
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发表时间：
2015-03
期刊：
影响因子：
4.5
通讯作者：
Tsunoda S
中科院分区：
文献类型：
--
作者：
Ping Y;Hahm ET;Waro G;Song Q;Vo-Ba DA;Licursi A;Bao H;Ganoe L;Finch K;Tsunoda S
Alzheimer’s disease (AD) is the most prevalent form of dementia in the elderly. β-amyloid (Aβ) accumulation in the brain is thought to be a primary event leading to eventual cognitive and motor dysfunction in AD. Aβ has been shown to promote neuronal hyperactivity, which is consistent with enhanced seizure activity in mouse models and AD patients. Little, however, is known about whether, and how, increased excitability contributes to downstream pathologies of AD. Here, we show that overexpression of human Aβ42 in a Drosophila model indeed induces increased neuronal activity. We found that the underlying mechanism involves the selective degradation of the A-type K+ channel, Kv4. An age-dependent loss of Kv4 leads to an increased probability of AP firing. Interestingly, we find that loss of Kv4 alone results in learning and locomotion defects, as well as a shortened lifespan. To test whether the Aβ42-induced increase in neuronal excitability contributes to, or exacerbates, downstream pathologies, we transgenically over-expressed Kv4 to near wild-type levels in Aβ42-expressing animals. We show that restoration of Kv4 attenuated age-dependent learning and locomotor deficits, slowed the onset of neurodegeneration, and partially rescued premature death seen in Aβ42-expressing animals. We conclude that Aβ42-induced hyperactivity plays a critical role in the age-dependent cognitive and motor decline of this Aβ42-Drosophila model, and possibly in AD. Alzheimer’s disease (AD) is the most prevalent form of dementia in the elderly population. While it is established that β-amyloid (Aβ) peptide accumulation is a primary even leading to AD, there is little known about how Aβ induces progressive neurodegeneration and decline in cognitive and motor function. Recently, over-production of Aβ has been shown to result in increased neuronal excitability, and Ca2+ “overload”, in hippocampal and cortical neurons. Increased excitability is also consistent with behavioral studies which have shown enhanced seizure activity in mouse models with increased Aβ expression, and increased risk of epilepsy in AD patients. We use a transgenic Drosophila model that expresses the secreted human Aβ42; this Aβ42-Drosophila line exhibits many of the hallmarks of AD. We show that the Aβ42-Drosophila line also displays increased neuronal excitability. We determine that the increase in excitability is due to the degradation of a specific K+ channel, Kv4. We then show that genetic restoration of Kv4 attenuates age-dependent learning and locomotor deficits, slows the onset of neurodegeneration, and partially rescues premature death seen in Aβ42-expressing animals. We conclude that Aβ42-induced hyperactivity plays a critical role in the age-dependent cognitive and motor decline of this Aβ42-Drosophila model, and possibly in AD.
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影响因子：
3.7
作者：
Iijima K;Chiang HC;Hearn SA;Hakker I;Gatt A;Shenton C;Granger L;Leung A;Iijima-Ando K;Zhong Y
通讯作者：
Zhong Y
影响因子：
1.9
作者：
HEISENBERG, M;BORST, A;BYERS, D
通讯作者：
BYERS, D
DOI：
10.1016/s0006-291x(84)80190-4
发表时间：
1984-01-01
影响因子：
3.1
作者：
GLENNER, GG;WONG, CW
通讯作者：
WONG, CW
DOI：
10.1007/s00359-004-0574-8
发表时间：
2005-03-01
影响因子：
2.1
作者：
Hendel, T;Michels, B;Gerber, B
通讯作者：
Gerber, B
影响因子：
16.2
作者：
Kamenetz, F;Tomita, T;Malinow, R
通讯作者：
Malinow, R