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Presynaptic dystrophic neurites surrounding amyloid plaques are sites of microtubule disruption, BACE1 elevation, and increased A? generation in Alzheimer's disease.

ABSTRACT: Alzheimer's disease (AD) is characterized by amyloid plaques composed of the ?-amyloid (A?) peptide surrounded by swollen presynaptic dystrophic neurites consisting of dysfunctional axons and terminals that accumulate the ?-site amyloid precursor protein (APP) cleaving enzyme (BACE1) required for A? generation. The cellular and molecular mechanisms that govern presynaptic dystrophic neurite formation are unclear, and elucidating these processes may lead to novel AD therapeutic strategies. Previous studies suggest A? may disrupt microtubules, which we hypothesize have a critical role in the development of presynaptic dystrophies. To investigate this further, here we have assessed the effects of A?, particularly neurotoxic A?42, on microtubules during the formation of presynaptic dystrophic neurites in vitro and in vivo. Live-cell imaging of primary neurons revealed that exposure to A?42 oligomers caused varicose and beaded neurites with extensive microtubule disruption, and inhibited anterograde and retrograde trafficking. In brain sections from AD patients and the 5XFAD transgenic mouse model of amyloid pathology, dystrophic neurite halos with BACE1 elevation around amyloid plaques exhibited aberrant tubulin accumulations or voids. At the ultrastructural level, peri-plaque dystrophies were strikingly devoid of microtubules and replete with multi-lamellar vesicles resembling autophagic intermediates. Proteins of the microtubule motors, kinesin and dynein, and other neuronal proteins were aberrantly localized in peri-plaque dystrophies. Inactive pro-cathepsin D also accumulated in peri-plaque dystrophies, indicating reduced lysosomal function. Most importantly, BACE1 accumulation in peri-plaque dystrophies caused increased BACE1 cleavage of APP and A? generation. Our study supports the hypothesis that A? induces microtubule disruption in presynaptic dystrophic neurites that surround plaques, thus impairing axonal transport and leading to accumulation of BACE1 and exacerbation of amyloid pathology in AD.

SUBMITTER: Sadleir KR

PROVIDER: S-EPMC4947125 | biostudies-literature | 2016 Aug

REPOSITORIES: biostudies-literature

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Presynaptic dystrophic neurites surrounding amyloid plaques are sites of microtubule disruption, BACE1 elevation, and increased Aβ generation in Alzheimer's disease.

Sadleir Katherine R KR Kandalepas Patty C PC Buggia-Prévot Virginie V Nicholson Daniel A DA Thinakaran Gopal G Vassar Robert R

Acta neuropathologica 20160318 2

Alzheimer's disease (AD) is characterized by amyloid plaques composed of the β-amyloid (Aβ) peptide surrounded by swollen presynaptic dystrophic neurites consisting of dysfunctional axons and terminals that accumulate the β-site amyloid precursor protein (APP) cleaving enzyme (BACE1) required for Aβ generation. The cellular and molecular mechanisms that govern presynaptic dystrophic neurite formation are unclear, and elucidating these processes may lead to novel AD therapeutic strategies. Previo ...[more]

PMID: 26993139

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Project description:The inter-relationship between microglia dynamics and oxidative stress (Ox-stress) in dystrophic neurites (DNs) at Alzheimer's Disease (AD) plaques may contribute to the pathological changes in neurons. We developed new in vivo imaging strategies to combine EGFP expression in microglia with neuronal expression of genetically encoded ratiometric redox sensors (rogRFP2 or roGFP1), and immunohistochemistry to investigate how microglia influence Ox-stress at amyloid plaques in 5xFAD AD mice. By simultaneously imaging microglia morphology and neuronal Ox-stress over time in vivo and in fixed brains we found that microglia preferentially enwrapped DNs exhibiting the greatest degree of Ox-stress. After microglia were partially depleted with the CSF1 receptor antagonist PLX3397, Ox-stress in DNs increased in a manner that was inversely correlated to the extent of coverage of the adjacent Aβ plaques by the remaining microglia. These data suggest that microglia do not create Ox-stress at Aβ plaques but instead create protective barriers around Aβ plaques possibly reducing the spread of Aβ. Intracranial injection of Aβ was sufficient to induce neuronal Ox-stress suggesting it to be the initial trigger of Ox-stress generation. Although Ox-stress is increased in DNs, neuronal survival is enhanced following microglia depletion indicating complex and multifactorial roles of microglia with both neurotoxic and neuroprotective components. Increased Ox-stress of DNs was correlated with higher LAMP1 and ubiquitin immunoreactivity supporting proposed mechanistic links between lysosomal accumulation in DNs and their intrinsic generation of Ox-stress. Our results suggest protective as well as neurotoxic roles for microglia at plaques and that the generation of Ox-stress of DNs could intrinsically be generated via lysosomal disruption rather than by microglia. In Brief: Simultaneous imaging of microglia and neuronal Ox-stress revealed a double-edged role for microglia in 5xFAD mice. Plaque associated microglia were attracted to and enwrapped Aβ plaques as well as the most highly oxidized DNs. After partial depletion of microglia, DNs were larger with greater levels of Ox-stress. Despite increased Ox-stress after microglia removal neuronal survival improved. Greater Ox-stress was correlated with increased levels of LAMP1 and ubiquitin thereby linking lysosome accumulation and Ox-stress in DNs.

Dataset Information

Presynaptic dystrophic neurites surrounding amyloid plaques are sites of microtubule disruption, BACE1 elevation, and increased A? generation in Alzheimer's disease.

Publications

Presynaptic dystrophic neurites surrounding amyloid plaques are sites of microtubule disruption, BACE1 elevation, and increased Aβ generation in Alzheimer's disease.

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