The innate immunity protein IFITM3 modulates γ-secretase in Alzheimer's disease.

Innate immunity is associated with Alzheimer's disease1, but the influence of immune activation on the production of amyloid-ß is unknown2,3. Here we identify interferon-induced transmembrane protein 3 (IFITM3) as a γ-secretase modulatory protein, and establish a mechanism by which inflammation affects the generation of amyloid-ß. Inflammatory cytokines induce the expression of IFITM3 in neurons and astrocytes, which binds to γ-secretase and upregulates its activity, thereby increasing the production of amyloid-ß. The expression of IFITM3 is increased with ageing and in mouse models that express familial Alzheimer's disease genes. Furthermore, knockout of IFITM3 reduces γ-secretase activity and the formation of amyloid plaques in a transgenic mouse model (5xFAD) of early amyloid deposition. IFITM3 protein is upregulated in tissue samples from a subset of patients with late-onset Alzheimer's disease that exhibit higher γ-secretase activity. The amount of IFITM3 in the γ-secretase complex has a strong and positive correlation with γ-secretase activity in samples from patients with late-onset Alzheimer's disease. These findings reveal a mechanism in which γ-secretase is modulated by neuroinflammation via IFITM3 and the risk of Alzheimer's disease is thereby increased.

Hypoxia Inducible Factor-1α binds and activates γ-secretase for Aß production under hypoxia and cerebral hypoperfusion.

Hypoxic-ischemic injury has been linked with increased risk for developing Alzheimer's disease (AD). The underlying mechanism of this association is poorly understood. Here, we report distinct roles for hypoxia-inducible factor-1α (Hif-1α) in the regulation of BACE1 and γ-secretase activity, two proteases involved in the production of amyloid-beta (Aß). We have demonstrated that Hif-1α upregulates both BACE1 and γ-secretase activity for Aß production in brain hypoxia-induced either by cerebral hypoperfusion or breathing 10% O2. Hif-1α binds to γ-secretase, which elevates the amount of active γ-secretase complex without affecting the level of individual subunits in hypoxic-ischemic mouse brains. Additionally, the expression of full length Hif-1α increases BACE1 and γ-secretase activity in primary neuronal culture, whereas a transcriptionally incompetent Hif-1α variant only activates γ-secretase. These findings indicate that Hif-1α transcriptionally upregulates BACE1 and nontranscriptionally activates γ-secretase for Aß production in hypoxic-ischemic conditions. Consequently, Hif-1α-mediated Aß production may be an adaptive response to hypoxic-ischemic injury, subsequently leading to increased risk for AD. Preventing the interaction of Hif-1α with γ-secretase may therefore be a promising therapeutic strategy for AD treatment.

Optical Nanosensor for Intracellular and Intracranial Detection of Amyloid-Beta.

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.

γ-Secretase Modulatory Proteins: The Guiding Hand Behind the Running Scissors.

Described as the "proteasome of the membrane" or the "scissors in the membrane," γ-secretase has notoriously complicated biology, and even after decades of research, the full extent of its regulatory mechanism remains unclear. γ-Secretase is an intramembrane aspartyl protease complex composed of four obligatory subunits: Nicastrin (NCT), Presenilin (PS), Presenilin Enhancer-2 (Pen-2), and Anterior pharynx-defective-1 (Aph-1). γ-Secretase cleaves numerous type 1 transmembrane substrates, with no apparent homology, and plays major roles in broad biological pathways such as development, neurogenesis, and cancer. Notch and the amyloid precursor protein (APP) and are undoubtedly the best-studied γ-secretase substrates because of their role in cancer and Alzheimer's disease (AD) and therefore became the focus of increasing studies as an attractive therapeutic target. The regulation of γ-secretase is intricate and involves the function of multiple cellular entities. Recently, γ-secretase modulatory proteins (GSMPs), which are non-essential subunits and yet modulate γ-secretase activity and specificity, have emerged as an important component in guiding γ-secretase. GSMPs are responsive to cellular and environmental changes and therefore, provide another layer of regulation of γ-secretase. This type of enzymatic regulation allows for a rapid and fine-tuning of γ-secretase activity when appropriate signals appear enabling a temporal level of regulation. In this review article, we discuss the latest developments on GSMPs and implications on the development of effective therapeutics for γ-secretase-associated diseases such as AD and cancer.

Author Correction: Hybrid PET/MRI enables high-spatial resolution, quantitative imaging of amyloid plaques in an Alzheimer's disease mouse model.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Hybrid PET/MRI enables high-spatial resolution, quantitative imaging of amyloid plaques in an Alzheimer's disease mouse model.

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.

Friend, Foe or Both? Immune Activity in Alzheimer's Disease.

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.

The role of astrocytes in amyloid production and Alzheimer's disease.

Alzheimer's disease (AD) is marked by the presence of extracellular amyloid beta (Aß) plaques, intracellular neurofibrillary tangles (NFTs) and gliosis, activated glial cells, in the brain. It is thought that Aß plaques trigger NFT formation, neuronal cell death, neuroinflammation and gliosis and, ultimately, cognitive impairment. There are increased numbers of reactive astrocytes in AD, which surround amyloid plaques and secrete proinflammatory factors and can phagocytize and break down Aß. It was thought that neuronal cells were the major source of Aß. However, mounting evidence suggests that astrocytes may play an additional role in AD by secreting significant quantities of Aß and contributing to overall amyloid burden in the brain. Astrocytes are the most numerous cell type in the brain, and therefore even minor quantities of amyloid secretion from individual astrocytes could prove to be substantial when taken across the whole brain. Reactive astrocytes have increased levels of the three necessary components for Aß production: amyloid precursor protein, ß-secretase (BACE1) and γ-secretase. The identification of environmental factors, such as neuroinflammation, that promote astrocytic Aß production, could redefine how we think about developing therapeutics for AD.