The Role of Astrocytes in Synapse Loss in Alzheimer's Disease: A Systematic Review.

Alzheimer's disease (AD) is the most common cause of dementia, affecting 35 million people worldwide. One pathological feature of progressing AD is the loss of synapses. This is the strongest correlate of cognitive decline. Astrocytes, as an essential part of the tripartite synapse, play a role in synapse formation, maintenance, and elimination. During AD, astrocytes get a reactive phenotype with an altered gene expression profile and changed function compared to healthy astrocytes. This process likely affects their interaction with synapses. This systematic review aims to provide an overview of the scientific literature including information on how astrocytes affect synapse formation and elimination in the brain of AD patients and in animal models of the disease. We review molecular and cellular changes in AD astrocytes and conclude that these predominantly result in lower synapse numbers, indicative of decreased synapse support or even synaptotoxicity, or increased elimination, resulting in synapse loss, and consequential cognitive decline, as associated with AD. Preventing AD induced changes in astrocytes might therefore be a potential therapeutic target for dementia. Systematic Review Registration: https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=148278, identifier [CRD148278].

Both male and female APPswe/PSEN1dE9 mice are impaired in spatial memory and cognitive flexibility at 9 months of age.

Alzheimer's disease (AD) is the most common cause of dementia. Despite many years of research, very limited treatment options are available. Here we aim to establish a well-defined learning and memory performance test for an AD mouse model, which can be used in future studies to evaluate the effect of novel drugs, treatments, and interventions. We exposed 9-month-old APPswe/PSEN1dE9 mice to a battery of memory tests to determine which test is best suited to study memory deficits in this specific AD mouse model. Since in more recent years it has become clear that there are sex-dependent differences in AD pathology, we also assessed differences in performance between male and female mice. From our test battery, we conclude that the Barnes maze task, which spans multiple days, is better suited to study subtle learning and memory deficits in 9-month-old APPswe/PS1dE9 mice, than the 2 trial T-maze and Fear conditioning task. This test revealed deficits in both spatial memory and cognitive flexibility in the APPswe/PS1dE9 mice compared to wildtype littermates. Furthermore, we conclude that there are no sex dependent memory deficit differences in this AD mouse model at this age.

Amyloid-ß plaques affect astrocyte Kir4.1 protein expression but not function in the dentate gyrus of APP/PS1 mice.

Alzheimer pathology is accompanied by astrogliosis. Reactive astrocytes surrounding amyloid plaques may directly affect neuronal communication, and one of the mechanisms by which astrocytes impact neuronal function is by affecting K+ homeostasis. Here we studied, using hippocampal slices from 9-month-old Alzheimer mice (APP/PS1) and wild-type littermates, whether astrocyte function is changed by analyzing Kir4.1 expression and function and astrocyte coupling in astrocytes surrounding amyloid-ß plaques. Immunohistochemical analysis of Kir4.1 protein in the dentate gyrus revealed localized increases in astrocytes surrounding amyloid-ß plaque deposits. We subsequently focused on changes in astrocyte function by using patch-clamp slice electrophysiology on both plaque- and non-plaque associated astrocytes to characterize general membrane properties. We found that Ba2+ -sensitive Kir4.1 conductance in astrocytes surrounding plaques was not affected by changes in Kir4.1 protein expression. Additional analysis of astrocyte gap junction coupling efficiency in the dentate gyrus revealed no apparent changes. Quantification of basic features of glutamatergic transmission to granule cells did not indicate disturbed neuronal communication in the dentate gyrus of APP/PS1 mice. Together, these results suggest that astrocytes in the dentate gyrus of APP/PS1 mice maintain their ability to buffer extracellular K+ and attempt to rectify imbalances in K+ concentration to maintain normal neuronal and synaptic function, possibly by localized increases in Kir4.1 protein expression. Our earlier transcriptomic data indicated that chronically activated astrocytes lose their neuronal support function. Here we show that, despite localized increased Kir4.1 protein expression, astrocyte Kir4.1 channel dysfunction is likely not involved in the pathogenesis of Alzheimer's disease.

Transcriptomic and functional analysis of Aß1-42 oligomer-stimulated human monocyte-derived microglia-like cells.

Dysregulation of microglial function contributes to Alzheimer's disease (AD) pathogenesis. Several genetic and transcriptome studies have revealed microglia specific genetic risk factors, and changes in microglia expression profiles in AD pathogenesis, viz. the human-Alzheimer's microglia/myeloid (HAM) profile in AD patients and the disease-associated microglia profile (DAM) in AD mouse models. The transcriptional changes involve genes in immune and inflammatory pathways, and in pathways associated with Aß clearance. Aß oligomers have been suggested to be the initial trigger of microglia activation in AD. To study the direct response to Aß oligomers exposure, we assessed changes in gene expression in an in vitro model for microglia, the human monocyte-derived microglial-like (MDMi) cells. We confirmed the initiation of an inflammatory profile following LPS stimulation, based on increased expression of IL1B, IL6, and TNFα. In contrast, the Aß1-42 oligomers did not induce an inflammatory profile or a classical HAM profile. Interestingly, we observed a specific increase in the expression of metallothioneins in the Aß1-42 oligomer treated MDMi cells. Metallothioneins are involved in metal ion regulation, protection against reactive oxygen species, and have anti-inflammatory properties. In conclusion, our data suggests that exposure to Aß1-42 oligomers may initially trigger a protective response in vitro.

Mechanical alterations of the hippocampus in the APP/PS1 Alzheimer's disease mouse model.

There is increasing evidence of altered tissue mechanics in neurodegeneration. However, due to difficulties in mechanical testing procedures and the complexity of the brain, there is still little consensus on the role of mechanics in the onset and progression of neurodegenerative diseases. In the case of Alzheimer's disease (AD), magnetic resonance elastography (MRE) studies have indicated viscoelastic differences in the brain tissue of AD patients and healthy controls. However, there is a lack of viscoelastic data from contact mechanical testing at higher spatial resolution. Therefore, we report viscoelastic maps of the hippocampus obtained by a dynamic indentation on brain slices from the APP/PS1 mouse model where individual brain regions are resolved. A comparison of viscoelastic parameters shows that regions in the hippocampus of the APP/PS1 mice are significantly stiffer than wild-type (WT) mice and have increased viscous dissipation. Furthermore, indentation mapping at the cellular scale directly on the plaques and their surroundings did not show local alterations in stiffness although overall mechanical heterogeneity of the tissue was high (SD∼40%).

Viscoelastic mapping of mouse brain tissue: Relation to structure and age.

There is growing evidence that mechanical factors affect brain functioning. However, brain components responsible for regulating the physiological mechanical environment are not completely understood. To determine the relationship between structure and stiffness of brain tissue, we performed high-resolution viscoelastic mapping by dynamic indentation of the hippocampus and the cerebellum of juvenile mice brains, and quantified relative area covered by neurons (NeuN-staining), axons (neurofilament NN18-staining), astrocytes (GFAP-staining), myelin (MBP-staining) and nuclei (Hoechst-staining) of juvenile and adult mouse brain slices. Results show that brain subregions have distinct viscoelastic parameters. In gray matter (GM) regions, the storage modulus correlates negatively with the relative area of nuclei and neurons, and positively with astrocytes. The storage modulus also correlates negatively with the relative area of myelin and axons (high cell density regions are excluded). Furthermore, adult brain regions are ∼ 20%-150% stiffer than the comparable juvenile regions which coincide with increase in astrocyte GFAP-staining. Several linear regression models are examined to predict the mechanical properties of the brain tissue based on (immuno)histochemical stainings.

PI 3-kinase delta enhances axonal PIP3 to support axon regeneration in the adult CNS.

Peripheral nervous system (PNS) neurons support axon regeneration into adulthood, whereas central nervous system (CNS) neurons lose regenerative ability after development. To better understand this decline whilst aiming to improve regeneration, we focused on phosphoinositide 3-kinase (PI3K) and its product phosphatidylinositol (3,4,5)-trisphosphate (PIP3 ). We demonstrate that adult PNS neurons utilise two catalytic subunits of PI3K for axon regeneration: p110α and p110δ. However, in the CNS, axonal PIP3 decreases with development at the time when axon transport declines and regenerative competence is lost. Overexpressing p110α in CNS neurons had no effect; however, expression of p110δ restored axonal PIP3 and increased regenerative axon transport. p110δ expression enhanced CNS regeneration in both rat and human neurons and in transgenic mice, functioning in the same way as the hyperactivating H1047R mutation of p110α. Furthermore, viral delivery of p110δ promoted robust regeneration after optic nerve injury. These findings establish a deficit of axonal PIP3 as a key reason for intrinsic regeneration failure and demonstrate that native p110δ facilitates axon regeneration by functioning in a hyperactive fashion.