Bereczki, E. | bioRxiv Science

bioRxiv2023

Early mitochondrial dysfunction proceeds neuroinflammation, synaptic alteration, and autophagy impairment in hippocampus of App knock-in Alzheimer mouse models

Increased amyloid {beta}-peptide (A{beta}) level is one of the drivers of Alzheimers disease (AD). Amyloid precursor protein (App) knock-in mice recapitulate the human A{beta} pathology, allowing the elucidation of the downstream effects of A{beta} and their temporal appearance upon disease progression. Here we have investigated the sequential onset of AD-like pathologies in the AppNL-F and AppNL-G-F knock-in mouse models by time-course transcriptome analysis of the hippocampus, a region severely affected in AD. Energy metabolism emerged as one of the most significantly altered pathways at an early stage of the development of the pathologies. Functional experiments in mitochondria isolated from AppNL-G-F brain subsequently identified upregulation of oxidative phosphorylation driven by the activity of mitochondrial complexes I, IV and V, combined with higher susceptibility to Ca2+-overload. This was followed by a strong neuroinflammatory response and impaired autophagy. Accumulation of autophagosomes and reduced number of mitochondria content in presynaptic terminals could account for the altered synapse morphology including increased number of synaptic vesicles and lowered thickness of post synaptic density in AppNL-G-F mice. This shows that A{beta}-induced pathways in the App knock-in mice recapitulate some key pathologies observed in AD brain, and our data herein contributes to the understanding of their timewise appearance and potential role in new therapeutic approaches.

neuroscience↗

bioRxiv2020

Presynaptic accumulation of α-synuclein causes synaptopathy and progressive neurodegeneration

Alpha-synuclein (-syn) mislocalisation and accumulation in intracellular inclusions is the major pathological hallmark of degenerative synucleinopathies, including Parkinsons disease, Parkinsons disease with Dementia and Dementia with Lewy Bodies. Typical symptoms are behavioural abnormalities including motor deficits that mark disease progression, while non-motor symptoms and synaptic deficits are already apparent during the early stages of disease. Synucleinopathies have therefore been considered synaptopathies that exhibit synaptic dysfunction prior to neurodegeneration. However, the mechanisms and events underlying synaptopathy are largely unknown. Here we investigated the cascade of pathological events underlying -syn accumulation and toxicity in a Drosophila model of synucleinopathy by employing a combination of histological, biochemical, behavioural and electrophysiological assays. Our findings demonstrate that targeted expression of human -syn leads to its accumulation in presynaptic terminals that caused downregulation of synaptic proteins, Cysteine String Protein, Synapsin, and Syntaxin 1A, and a reduction in the number of Bruchpilot puncta, the core component of the presynaptic active zone essential for its structural integrity and function. These -syn-mediated presynaptic alterations resulted in impaired neuronal function, which triggered behavioural deficits in ageing Drosophila that occurred prior to progressive degeneration of dopaminergic neurons. Comparable alterations in presynaptic active zone protein were found in patient brain samples of Dementia with Lewy Bodies. Together, these findings demonstrate that presynaptic accumulation of -syn impairs the active zone and neuronal function, which together cause synaptopathy that results in behavioural deficits and the progressive loss of dopaminergic neurons. This sequence of events resembles the cytological and behavioural phenotypes that characterise the onset and progression of synucleinopathies, suggesting that -syn mediated synaptopathy is an initiating cause of age-related neurodegeneration.

neuroscience↗