ABSTRACT
Alzheimer's disease (AD) is characterized by the presence of amyloid beta (Aß) plaques and neurofibrillary tangles (NFTs), neuronal and synaptic loss and inflammation of the central nervous system (CNS). The majority of AD research has been dedicated to the understanding of two major AD hallmarks (i.e. Aß and NFTs); however, recent genome-wide association studies (GWAS) data indicate neuroinflammation as having a critical role in late-onset AD (LOAD) development, thus unveiling a novel avenue for AD therapeutics. Recent evidence has provided much support to the innate immune system's involvement with AD progression; however, much remains to be uncovered regarding the role of glial cells, specifically microglia, in AD. Moreover, numerous variants in immune and/or microglia-related genes have been identified in whole-genome sequencing and GWAS analyses, including such genes as TREM2, CD33, APOE, API1, MS4A, ABCA7, BIN1, CLU, CR1, INPP5D, PICALM and PLCG2. In this review, we aim to provide an insight into the function of the major LOAD-associated microglia response genes.
Subject(s)
Alzheimer Disease , Microglia , Alzheimer Disease/genetics , Amyloid beta-Peptides/genetics , Central Nervous System , Genome-Wide Association Study , Humans , Membrane Glycoproteins , Receptors, Immunologic/geneticsABSTRACT
Amyloid-beta (Aß) deposition occurs in the early stages of Alzheimer's disease (AD), but the early detection of Aß is a persistent challenge. Herein, we engineered a near-infrared optical nanosensor capable of detecting Aß intracellularly in live cells and intracranially in vivo. The sensor is composed of single-walled carbon nanotubes functionalized with Aß wherein Aß-Aß interactions drive the response. We found that the Aß nanosensors selectively responded to Aß via solvatochromic modulation of the near-infrared emission of the nanotube. The sensor tracked Aß accumulation in live cells and, upon intracranial administration in a genetic model of AD, signaled distinct responses in aged mice. This technology enables the interrogation of molecular mechanisms underlying Aß neurotoxicity in the development of AD in living systems.
Subject(s)
Alzheimer Disease , Nanotubes, Carbon , Animals , Mice , Amyloid beta-Peptides , Alzheimer Disease/diagnostic imaging , Alzheimer Disease/geneticsABSTRACT
An amendment to this paper has been published and can be accessed via a link at the top of the paper.
ABSTRACT
The emergence of PET probes for amyloid plaques and neurofibrillary tangles, hallmarks of Alzheimer disease (AD), enables monitoring of pathology in AD mouse models. However, small-animal PET imaging is limited by coarse spatial resolution. We have installed a custom-fabricated PET insert into our small-animal MRI instrument and used PET/MRI hybrid imaging to define regions of amyloid vulnerability in 5xFAD mice. We compared fluorine-18 [18F]-Florbetapir uptake in the 5xFAD brain by dedicated small-animal PET/MRI and PET/CT to validate the quantitative measurement of PET/MRI. Next, we used PET/MRI to define uptake in six brain regions. As expected, uptake was comparable to wild-type in the cerebellum and elevated in the cortex and hippocampus, regions implicated in AD. Interestingly, uptake was highest in the thalamus, a region often overlooked in AD studies. Development of small-animal PET/MRI enables tracking of brain region-specific pathology in mouse models, which may prove invaluable to understanding AD progression and therapeutic development.
Subject(s)
Alzheimer Disease/pathology , Disease Models, Animal , Hippocampus/pathology , Magnetic Resonance Imaging/methods , Plaque, Amyloid/pathology , Positron-Emission Tomography/methods , Thalamus/pathology , Alzheimer Disease/diagnostic imaging , Alzheimer Disease/metabolism , Animals , Fluorine Radioisotopes/metabolism , Hippocampus/diagnostic imaging , Hippocampus/metabolism , Mice , Mice, Inbred C57BL , Plaque, Amyloid/diagnostic imaging , Plaque, Amyloid/metabolism , Radiopharmaceuticals/metabolism , Thalamus/diagnostic imaging , Thalamus/metabolismABSTRACT
Alzheimer's disease (AD) is marked by the presence of amyloid beta (Aß) plaques, neurofibrillary tangles (NFT), neuronal death and synaptic loss, and inflammation in the brain. AD research has, in large part, been dedicated to the understanding of Aß and NFT deposition as well as to the pharmacological reduction of these hallmarks. However, recent GWAS data indicates neuroinflammation plays a critical role in AD development, thereby redirecting research efforts toward unveiling the complexities of AD-associated neuroinflammation. It is clear that the innate immune system is intimately associated with AD progression, however, the specific roles of glia and neuroinflammation in AD pathology remain to be described. Moreover, inflammatory processes have largely been painted as detrimental to AD pathology, when in fact, many immune mechanisms such as phagocytosis aid in the reduction of AD pathologies. In this review, we aim to outline the delicate balance between the beneficial and detrimental aspects of immune activation in AD as a more thorough understanding of these processes is critical to development of effective therapeutics for AD.