The incidence of Alzheimer’s disease (AD), the leading cause of dementia, increases rapidly with age, but why age constitutes the main risk factor is still poorly understood. Brain ageing affects oligodendrocytes and the structural integrity of myelin sheaths¹, the latter of which is associated with secondary neuroinflammation^2,3. As oligodendrocytes support axonal energy metabolism and neuronal health^4–7, we hypothesized that loss of myelin integrity could be an upstream risk factor for neuronal amyloid-β (Aβ) deposition, the central neuropathological hallmark of AD. Here we identify genetic pathways of myelin dysfunction and demyelinating injuries as potent drivers of amyloid deposition in mouse models of AD. Mechanistically, myelin dysfunction causes the accumulation of the Aβ-producing machinery within axonal swellings and increases the cleavage of cortical amyloid precursor protein. Suprisingly, AD mice with dysfunctional myelin lack plaque-corralling microglia despite an overall increase in their numbers. Bulk and single-cell transcriptomics of AD mouse models with myelin defects show that there is a concomitant induction of highly similar but distinct disease-associated microglia signatures specific to myelin damage and amyloid plaques, respectively. Despite successful induction, amyloid disease-associated microglia (DAM) that usually clear amyloid plaques are apparently distracted to nearby myelin damage. Our data suggest a working model whereby age-dependent structural defects of myelin promote Aβ plaque formation directly and indirectly and are therefore an upstream AD risk factor. Improving oligodendrocyte health and myelin integrity could be a promising target to delay development and slow progression of AD.

Transgenic mouse models represent an essential tool for the exploration of Alzheimer’s disease (AD) pathological mechanisms and the development of novel treatments, which at present provide only symptomatic and transient effects. While a variety of mouse models successfully reflects the main neuropathological hallmarks of AD, such as extracellular amyloid-β (Aβ) deposits, intracellular accumulation of Tau protein, the development of micro- and astrogliosis, as well as behavioral deficits, substantial neuron loss, as a key feature of the disease, seems to be more difficult to achieve. In this review, we summarize information on classic and more recent transgenic mouse models for AD, focusing in particular on loss of pyramidal, inter-, and cholinergic neurons. Although the cause of neuron loss in AD is still a matter of scientific debate, it seems to be linked to intraneuronal Aβ accumulation in several transgenic mouse models, especially in pyramidal neurons.

Introduction: Alzheimer’s disease (AD) is characterized by a cerebral accumulation and aggregation of amyloid-β (Aβ) peptides, which mainly accumulate in the form of extracellular deposits. In addition to the well-described full-length peptides Aβ_1-40 and Aβ_1-42, a variety of amino- and carboxy-terminally truncated Aβ variants has been identified in brain samples from sporadic and familial AD cases. Areas covered: This review gives an overview on the role of truncated Aβ species in human AD, as well as in transgenic AD mouse models. We outline the relevance of the most abundant N- and C-truncated Aβ species, highlight potential mechanisms with regard to their generation and discuss their suitability as targets for pharmacological interventions. Expert opinion: A variety of recent clinical trials aiming either at a reduced Aβ production by the use of secretase inhibitors or at increased Aβ clearance by the use of immunotherapy were terminated unsuccessful. Truncated or post-translationally modified Aβ peptides are becoming increasingly recognized as important players in the etiology of AD and a more thorough comprehension of their cellular origin and biochemical peculiarities might break new ground for therapeutic strategies.

Infantile-onset RNaseT2 deficient leukoencephalopathy is characterised by cystic brain lesions, multifocal white matter alterations, cerebral atrophy, and severe psychomotor impairment. The phenotype is similar to congenital cytomegalovirus brain infection and overlaps with type I interferonopathies, suggesting a role for innate immunity in its pathophysiology. To date, pathophysiological studies have been hindered by the lack of mouse models recapitulating the neuroinflammatory encephalopathy found in patients. In this study, we generated Rnaset2^−/− mice using CRISPR/Cas9-mediated genome editing. Rnaset2^−/− mice demonstrate upregulation of interferon-stimulated genes and concurrent IFNAR1-dependent neuroinflammation, with infiltration of CD8⁺ effector memory T cells and inflammatory monocytes into the grey and white matter. Single nuclei RNA sequencing reveals homeostatic dysfunctions in glial cells and neurons and provide important insights into the mechanisms of hippocampal-accentuated brain atrophy and cognitive impairment. The Rnaset2^−/− mice may allow the study of CNS damage associated with RNaseT2 deficiency and may be used for the investigation of potential therapies.

Aims: The deposition of amyloid‐β (Aβ) peptides in the form of extracellular plaques in the brain represents one of the classical hallmarks of Alzheimer’s disease (AD). In addition to ‘full‐length’ Aβ starting with aspartic acid (Asp‐1), considerable amounts of various shorter, N‐terminally truncated Aβ peptides have been identified by mass spectrometry in autopsy samples from individuals with AD.Methods: Selectivity of several antibodies detecting full‐length, total or N‐terminally truncated Aβ species has been characterized with capillary isoelectric focusing assays using a set of synthetic Aβ peptides comprising different N‐termini. We further assessed the N‐terminal heterogeneity of extracellular and vascular Aβ peptide deposits in the human brain by performing immunohistochemical analyses using sporadic AD cases with antibodies targeting different N‐terminal residues, including the biosimilar antibodies Bapineuzumab and Crenezumab.Results: While antibodies selectively recognizing Aβ_1–x showed a much weaker staining of extracellular plaques and tended to accentuate cerebrovascular amyloid deposits, antibodies detecting Aβ starting with phenylalanine at position 4 of the Aβ sequence showed abundant amyloid plaque immunoreactivity in the brain parenchyma. The biosimilar antibody Bapineuzumab recognized Aβ starting at Asp‐1 and demonstrated abundant immunoreactivity in AD brains.Discussion: In contrast to other studied Aβ_1–x‐specific antibodies, Bapineuzumab displayed stronger immunoreactivity on fixed tissue samples than with sodium dodecyl sulfate‐denatured samples on Western blots. This suggests conformational preferences of this antibody. The diverse composition of plaques and vascular deposits stresses the importance of understanding the roles of various Aβ variants during disease development and progression in order to generate appropriate target‐developed therapies.