Abstract
BackgroundA devastating aspect of Alzheimer's disease (AD) is the progressive deterioration of memory due to neuronal loss. Amyloid precursor protein (APP) occupies a central position in AD and APP-derived amyloid-β (Aβ) peptides are thought to play a pivotal role in disease pathogenesis. Nonetheless, it is becoming clear that AD etiology is highly complex and that factors other than Aβ also contribute to AD pathogenesis. APP intracellular domain (AICD) is generated together with Aβ and we recently showed that AICD transgenic mice recapitulate pathological features of AD such as tau hyperphosphorylation, memory deficits and neurodegeneration without increasing the Aβ levels. Since impaired adult neurogenesis is shown to augment memory deficits in AD mouse models, here we examined the status of adult neurogenesis in AICD transgenic mice.Methodology/Principal FindingWe previously generated transgenic mice co-expressing 59-residue long AICD fragment and its binding partner Fe65. Hippocampal progenitor cell proliferation was determined by BrdU incorporation at 1.5, 3 and 12 months of age. Only male transgenic and their respective wilt type littermate control mice were used. We find age-dependent decrease in BrdU incorporation and doublecortin-positive cells in the dentate gyrus of AICD transgenic mice suggesting impaired adult neurogenesis. This deficit resulted from decreased proliferation and survival, whereas neuronal differentiation remained unaffected. Importantly, this impairment was independent of Aβ since APP-KO mice expressing AICD also exhibit reduced neurogenesis. The defects in adult neurogenesis are prevented by long-term treatment with the non-steroidal anti-inflammatory agents ibuprofen or naproxen suggesting that neuroinflammation is critically involved in impaired adult neurogenesis in AICD transgenic mice.Conclusion/SignificanceSince adult neurogenesis is crucial for spatial memory, which is particularly vulnerable in AD, these findings suggest that AICD can exacerbate memory defects in AD by impairing adult neurogenesis. Our findings further establish that AICD, in addition to Aβ, contributes to AD pathology and that neuroinflammation plays a much broader role in AD pathogenesis than previously thought.
Highlights
Alzheimer’s disease (AD) is a progressive neurodegenerative disorder characterized by a gradual decline in memory and executive functions
Conclusion/Significance: Since adult neurogenesis is crucial for spatial memory, which is vulnerable in AD, these findings suggest that APP intracellular domain (AICD) can exacerbate memory defects in AD by impairing adult neurogenesis
Animals older than 12 months were not studied because at this stage even the wild-type mice showed a very low level of adult neurogenesis. These data suggest that AICD impairs adult hippocampal progenitor cell (HPC) proliferation in vivo
Summary
Alzheimer’s disease (AD) is a progressive neurodegenerative disorder characterized by a gradual decline in memory and executive functions. Mounting evidence suggests Amyloid precursor protein (APP) and presenilins are central molecules in the pathophysiology of AD [1,2]. Ab peptides are shown to hyperphosphorylate tau [3], induce neuronal cell death in vitro, and cause memory deficits in mice [4]. They are implicated in causing silent seizures [5] and in the impairment of adult neurogenesis in AD mouse models [6,7,8,9,10]. Amyloid precursor protein (APP) occupies a central position in AD and APP-derived amyloid-b (Ab) peptides are thought to play a pivotal role in disease pathogenesis. Since impaired adult neurogenesis is shown to augment memory deficits in AD mouse models, here we examined the status of adult neurogenesis in AICD transgenic mice
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