Abstract
Alzheimer’s disease (AD) is characterized by the deposition of β-amyloid (Aβ) senile plaques and tau-associated neurofibrillary tangles. Other disease features include neuroinflammation and cholinergic neurodegeneration, indicating their possible importance in disease propagation. Recent studies have shown that monocytic cells can migrate into the AD brain toward Aβ plaques and reduce plaque burden. The purpose of this study was to evaluate whether the administration of intravenous infusions of ‘young’ CD11b-positive (+) monocytes into an AD mouse model can enhance Aβ plaque clearance and attenuate cognitive deficits. Peripheral monocytes were isolated from two-week-old wildtype mice using the Pluriselect CD11b+ isolation method and characterized by FACS analysis for surface marker expression and effective phagocytosis of 1 μm fluorescent microspheres, FITC-Dextran or FITC-Aβ1–42. The isolated monocytes were infused via the tail vein into a transgenic AD mouse model, which expresses the Swedish, Dutch/Iowa APP mutations (APPSwDI). The infusions began when animals reached 5 months of age, when little plaque deposition is apparent and were repeated again at 6 and 7 months of age. At 8 months of age, brains were analyzed for Aβ+ plaques, inflammatory processes and microglial (Iba1) activation. Our data show that infusions of two-week-old CD11b+ monocytes into adult APPSwDI mice results in a transient improvement of memory function, a reduction (30%) in Aβ plaque load and significantly in small (<20 μm) and large (>40 μm) plaques. In addition, we observe a reduction in Iba1+ cells, as well as no marked elevations in cytokine levels or other indicators of inflammation. Taken together, our findings indicate that young CD11b+ monocytes may serve as therapeutic candidates for improved Aβ clearance in AD.
Highlights
Alzheimer’s disease (AD) is a progressive neurodegenerative disease characterized by the deposition of tau-associated neurofibrillary tangles and senile plaques, composed of β-amyloid (Aβ), activated microglia, reactive astrocytes, and dystrophic neurons and synapses [1]
We investigated the effects of CD11b+ monocytes infused into the APPSwDI AD transgenic mouse model
Peripheral blood mouse monocytes were collected from the periphery of young (2 weeks; Fig. 2A) and adult (6 months, Fig. 2B) mice and subsequently evaluated for surface marker expression and functional properties
Summary
Alzheimer’s disease (AD) is a progressive neurodegenerative disease characterized by the deposition of tau-associated neurofibrillary tangles and senile plaques, composed of β-amyloid (Aβ), activated microglia, reactive astrocytes, and dystrophic neurons and synapses [1]. Convincing evidence indicates that the infiltration of monocyte-derived cells (i.e. monocytes and macrophages) from the periphery into the CNS and perivascular spaces may help restrict amyloid deposition and prevent cognitive decline [4,5,6]. These studies have shown that bone marrow-derived cells or monocytes are recruited to the brain (triggered by Aβ40 or Aβ42) and can restrict amyloid plaque deposition in AD transgenic mice [7,8]. These findings indicate that the administration and subsequent recruitment of peripheral monocytic cells into the brain may have important implications for future AD therapies
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