Alzheimer's disease (AD) is the most common dementia, and is hallmarked by deposition of A? peptides as 'senile'?-amyloid plaques, neuropathology, and neuroinflammation. Toll-like receptors (TLRs) are germline- encoded sensors of pathogens by cells of the innate immune system and play differential roles in amyloid homeostasis. TLRs transduce their signals through the serine/threonine IL-1 receptor-associated kinase (IRAK). The IRAK family is chiefly comprised of kinases that positively regulate TLR signaling, with the notable exception of the inhibitory kinase, IRAK-M. IRAK-M expression is specific to cells of monocytic lineage, including microglia, and plays a critical role in keeping innate immune responses in check. To test whether IRAK-M participated in cerebral amyloid remodeling, we crossed mice deficient in IRAK-M (IRAK-M-/-) with mice over expressing mutant human amyloid precursor protein, the APPPS1 mouse model of cerebral amyloidosis. We then evaluated the state of immune cell activation and cerebral A? burden in age and sex- matched littermates from three groups: APPPS1-IRAK-M+/+, APPPS1-IRAK-M-/+, and APPPS1-IRAK-M-/- mice. Preliminary data showed a gene dose-dependent effect where microglial activation inversely correlated with IRAK-M allele number. Further, brain parenchymal A? abundance was correspondingly attenuated in APPPS1- IRAK-M-/- mice as measured by biochemical approaches. Interestingly, confocal imaging of APPPS1- IRAK-M-/- mouse brains revealed A? colocalization with the lysosomal marker LAMP1, suggesting a phagocytic mechanism of IRAK-M-/- microglia-mediated A? clearance. This proposal is designed to test whether disinhibition of IRAK-M affects microglial remodeling of amyloid pathology. The focus of Specific Aim 1 will be to further characterize brain pathology and animal behavior in IRAK-M deficient Alzheimer mice. The proposed experiments will elucidate the impact of IRAK-M deficiency on the microglial response to Alzheimer- like pathology, including its influence on cognitive impairment. We will then evaluate cytokine/chemokine responses in vivo to determine the whether IRAK-M deficiency promotes pro- or anti-inflammatory reactions of microglia in APPPS1-IRAK-M-/- mice.
Specific Aim 2 will further assess phagocytosis of A? in APPPS1-IRAK- M-/- microglia and determine the function of IRAK-M in A? phagocytosis. The applicant is a third-year doctoral student in the laboratory of Dr. Terrence Town, who has been working in the field of AD innate immunology for the past 17 years. The proposed training plan outlines a set of career development activities and scientific workshops - e.g. advanced education in neuropathology, animal behavior and grant writing - to facilitate completion of this work.
There are now over 3 million Americans afflicted with Alzheimer's disease, a figure that is projected to increase to 9 million by 2050, underscoring a rapidly developing public health problem. We propose that genetic ablation of IRAK-M in innate immune cells allows these cells to restrict the disease by phagocytic clearance of amyloid-?. These results could establish the importance of IRAK-M in Alzheimer's pathogenesis and further elucidate the role of innate immune cells in the disease.
|Gate, David; Danielpour, Moise; Rodriguez Jr, Javier et al. (2014) T-cell TGF-? signaling abrogation restricts medulloblastoma progression. Proc Natl Acad Sci U S A 111:E3458-66|