Selective suppression of oligodendrocyte-derived amyloid beta rescues neuronal dysfunction in Alzheimer’s disease

Funding: Funding: R.M.R, D.K., C.S.F. and M.A.B. are supported by the UK Dementia Research Institute through UK DRI Ltd, principally funded by the UK Medical Research Council. M.A.B. is further supported by an UKRI Future Leaders Fellowship (MR/X011038/1) and an NC3Rs studentship grant (NC/W001675/1). S.S.H. is supported by an Alzheimer’s Association International Research Fellowship (AARF-23-1149637). C.A. and S.W. are supported by the National Institute for Health and Care Research University College London Hospitals Biomedical Research Centre. M.S. is supported by an MRC Career Development Award (MR/X019977/1). T.A.G. is supported by an Alzheimer’s Association Research Fellowship to Promote Diversity (23AARFD-1029918).Reduction of amyloid beta (Aβ) has been shown to be effective in treating Alzheimer’s disease (AD), but the underlying assumption that neurons are the main source of pathogenic Aβ is untested. Here, we challenge this prevailing belief by demonstrating that oligodendrocytes are an important source of Aβ in the human brain and play a key role in promoting abnormal neuronal hyperactivity in an AD knock-in mouse model. We show that selectively suppressing oligodendrocyte Aβ production improves AD brain pathology and restores neuronal function in the mouse model in vivo. Our findings suggest that targeting oligodendrocyte Aβ production could be a promising therapeutic strategy for treating AD.Peer reviewe

PolyGR and polyPR knock-in mice reveal a conserved neuroprotective extracellular matrix signature in C9orf72 ALS/FTD neurons

Dipeptide repeat proteins are a major pathogenic feature of C9orf72 amyotrophic lateral sclerosis (C9ALS)/frontotemporal dementia (FTD) pathology, but their physiological impact has yet to be fully determined. Here we generated C9orf72 dipeptide repeat knock-in mouse models characterized by expression of 400 codon-optimized polyGR or polyPR repeats, and heterozygous C9orf72 reduction. (GR)400 and (PR)400 knock-in mice recapitulate key features of C9ALS/FTD, including cortical neuronal hyperexcitability, age-dependent spinal motor neuron loss and progressive motor dysfunction. Quantitative proteomics revealed an increase in extracellular matrix (ECM) proteins in (GR)400 and (PR)400 spinal cord, with the collagen COL6A1 the most increased protein. TGF-β1 was one of the top predicted regulators of this ECM signature and polyGR expression in human induced pluripotent stem cell neurons was sufficient to induce TGF-β1 followed by COL6A1. Knockdown of TGF-β1 or COL6A1 orthologues in polyGR model Drosophila exacerbated neurodegeneration, while expression of TGF-β1 or COL6A1 in induced pluripotent stem cell-derived motor neurons of patients with C9ALS/FTD protected against glutamate-induced cell death. Altogether, our findings reveal a neuroprotective and conserved ECM signature in C9ALS/FTD.</p

Tipping the Scales: Peptide-Dependent Dysregulation of Neural Circuit Dynamics in Alzheimer's Disease

Identifying effective treatments for Alzheimer's disease (AD) has proven challenging and has instigated a shift in AD research focus toward the earliest disease-initiating cellular mechanisms. A key insight has been an increase in soluble Aβ oligomers in early AD that is causally linked to neuronal and circuit hyperexcitability. However, other accumulating AD-related peptides and proteins, including those derived from the same amyloid precursor protein, such as Aη or sAPPα, and autonomously, such as tau, exhibit surprising opposing effects on circuit dynamics. We propose that the effects of these on neuronal circuits have profound implications for our understanding of disease complexity and heterogeneity and for the development of personalized diagnostic and therapeutic strategies in AD. Here, we highlight important peptide-specific mechanisms of dynamic pathological disequilibrium of cellular and circuit activity in AD and discuss approaches in which these may be further understood, and theoretically and experimentally leveraged, to elucidate AD pathophysiology.status: publishe

Neuronal excitation/inhibition imbalance: core element of a translational perspective on Alzheimer pathophysiology

Our incomplete understanding of the link between Alzheimer’s Disease pathology and symptomatology is a crucial obstacle for therapeutic success. Recently, translational studies have begun to connect the dots between protein alterations and deposition, brain network dysfunction and cognitive deficits. Disturbance of neuronal activity, and in particular an imbalance in underlying excitation/inhibition (E/I), appears early in AD, and can be regarded as forming a central link between structural brain pathology and cognitive dysfunction. While there are emerging (non-)pharmacological options to influence this imbalance, the complexity of human brain dynamics has hindered identification of an optimal approach. We suggest that focusing on the integration of neurophysiological aspects of AD at the micro-, meso- and macroscale, with the support of computational network modeling, can unite fundamental and clinical knowledge, provide a general framework, and suggest rational therapeutic targets

Breakdown of slow-wave oscilliations in mouse modles of Alzheimer's disease

Alzheimer´s disease (AD) causes devastating impairments in long-term memory1. In the healthy brain, memory consolidation crucially depends on slow-wave oscillations2-4 that are generated during sleep5 in interconnected large-scale neuronal networks, including the neocortex and the hippocampus6-8. Functional magnetic resonance imaging (fMRI) studies indicate that in AD patients, the functional connectivity between distant brain regions is massively impaired9-11. However, the consequences of these impairments for temporally coordinated brain activities, such as slow-wave oscillations, are unknown. Here, we implemented a method of large-scale brain calcium fluorescence imaging to analyze slow-wave activity across widely distributed neuronal networks in the neocortex and hippocampus of transgenic mouse models of AD in vivo. The results demonstrate a strong impairment of slow-wave activity, with a severe breakdown of its long-range coherence within the cortex as well as between cortex and hippocampus of transgenic mice. Similar impairments can be induced in wild-type mice by direct application of exogenous amyloid-ß (Aß) peptides. The coherence of cortical activity can be restored, both in transgenic and in Aß-treated animals, by enhancing GABAAergic inhibition with benzodiazepines. Together, our results reveal a causal link between pathologically high levels of Aß, neuronal disinhibition and the breakdown of slow-wave activity in the diseased brain

Pearls & Oy-sters: Ocular motor apraxia as essential differential diagnosis to supranuclear gaze palsy: Eyes up

Ocular motor apraxia (OA) is an inability to initiate voluntary saccades in a head-fixed position, while saccades can be initiated by the vestibulo-ocular reflex (indicating dysfunction in the frontal eye fields)

Decreased amyloid-β but increased neuronal hyperactivity by immunotherapy in Alzheimer´s models

Among the most promising approaches to treat Alzheimer´s disease (AD) is immunotherapy with amyloid-β (Aβ)-targeting antibodies. Here, by using in vivo twophoton imaging in mouse models, we demonstrate that two different anti-Aβ antibodies used for treatment are ineffective in repairing neuronal dysfunction and can cause an increase in cortical hyperactivity. This unexpected finding provides a possible cellular explanation for the lack of cognitive improvement by immunotherapy in human studies