Dystrophic peptidergic neurites in senile plaques of Alzheimer's disease hippocampus precede formation of paired helical filaments

Lenders, Marie-Berthe; Peers, Marie-Claire; Tramu, G.; Delacourte, André; Défossez, A.; Petit, H; Mazzuca, M

doi:10.1016/0006-8993(89)90812-3

Cited by 28 publications

(13 citation statements)

References 29 publications

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“…In the spinal cord (Fig. 3D), the motor neurons of the anterior horn also exhibited disorganized patterns, with a characteristic ballooned morphology of dystrophic fibers [47]. As shown in Figs.…”

Section: Resultsmentioning

confidence: 73%

NRF2 deficiency replicates transcriptomic changes in Alzheimer's patients and worsens APP and TAU pathology

et al. 2017

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Failure to translate successful neuroprotective preclinical data to a clinical setting in Alzheimer's disease (AD) indicates that amyloidopathy and tauopathy alone provide an incomplete view of disease. We have tested here the relevance of additional homeostatic deviations that result from loss of activity of transcription factor NRF2, a crucial regulator of multiple stress responses whose activity declines with ageing. A transcriptomic analysis demonstrated that NRF2-KO mouse brains reproduce 7 and 10 of the most dysregulated pathways of human ageing and AD brains, respectively. Then, we generated a mouse that combines amyloidopathy and tauopathy with either wild type (AT-NRF2-WT) or NRF2-deficiency (AT-NRF2-KO). AT-NRF2-KO brains presented increased markers of oxidative stress and neuroinflammation as well as higher levels of insoluble phosphorylated-TAU and Aβ*56 compared to AT-NRF2-WT mice. Young adult AT-NRF2-KO mice exhibited deficits in spatial learning and memory and reduced long term potentiation in the perforant pathway. This study demonstrates the relevance of normal homeostatic responses that decline with ageing, such as NRF2 activity, in the protection against proteotoxic, inflammatory and oxidative stress and provide a new strategy to fight AD.

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Section: Resultsmentioning

confidence: 73%

NRF2 deficiency replicates transcriptomic changes in Alzheimer's patients and worsens APP and TAU pathology

et al. 2017

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“…However, the accumulation of synucleins in dystrophic neurites appears more restricted to the above diseases, especially in the case of β- and γ-synucleins. Dystrophic neurites occurring in AD cases are found to trap many proteins, including ubiquitin, APP and neurofilament proteins, but the accumulation of these proteins is mainly due to the deposition of amyloid plaques (Lenders et al, 1989;Cras et al, 1991;Shoji et al, 1990). In this study, we have found that the population of dystrophic neurites marked by ubiquitin, SMI31 and APP is rarely detected in mouse brain at the age of 15 months, but appeared in a clustered form in much older mice (24-month-old), in line with previous observations (Migheli et al, 1992;Vickers et al, 1996).…”

Section: Discussionmentioning

confidence: 99%

“…For example, dystrophic neurites in the brains of patients with Alzheimer’s disease (AD) are found mainly in the area surrounding neuritic amyloid plaques (Dickson et al, 1988;Lenders et al, 1989;Onorato et al, 1989;Hu et al, 2007). Morphological characterizations of dystrophic neurites in AD brains have been extensively described, and many proteins, including ubiquitin (Kowall and Kosik, 1987;Onorato et al, 1989;Perry et al, 1987) and GAP-43 (Masliah et al, 1992) can mark dystrophic neurites.…”

Section: Introductionmentioning

confidence: 99%

The Occurrence of Aging-Dependent Reticulon 3 Immunoreactive Dystrophic Neurites Decreases Cognitive Function

Shi¹,

Hu²,

Prior³

et al. 2009

J. Neurosci.

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Reticulon 3 (RTN3) has been shown to mark a distinct and abundant population of dystrophic neurites named RTN3 immunoreactive dystrophic neurites (RIDNs) in patients' brains of Alzheimer disease (AD). Transgenic mice expressing RTN3 (Tg-RTN3) also spontaneously develop RIDNs. To determine whether RIDNs formed in Tg-RTN3 mice would ever naturally occur in the nontransgenic mouse brain, we targeted our examination to elderly mouse brains on the basis that AD is an age-dependent neurodegenerative disease where the decline in cognitive function becomes progressively increased during the course of the disease. Here, we demonstrate that the distribution of RIDNs is abundant, rather than sporadic, in elderly but not young mouse brains. RIDNs in the elderly brain have two distinct populations: abundantly dispersed RIDNs that can only be marked by RTN3, and less abundantly clustered RIDNs that can be marked by multiple proteins including RTN3, ubiquitin, and phosphorylated neurofilament. The abundance of RIDNs in Tg-RTN3 mice at the age of 3 months resembles that of 24-month-old wild type mice, suggesting that this animal model mimics and accelerates the natural occurrence of RIDNs. Importantly, we demonstrate that preformed RIDNs appear to reduce dendritic spine density and synaptic function. Further analysis from mechanistic studies suggests that elevated levels of RTN3 lead to an imbalance in the axonal transport of RTN3, which results in the accumulation of RTN3 in swollen neurites. Collectively, these results suggest that blocking the formation of RIDNs may be a promising strategy to impede cognitive decline in the elderly and in AD patients.

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“…Dystrophic axons from completely different afferent sources, expressing distinct neurotransmitters, have been shown to be present in particular NPs (276, 277), which strongly implies that toxicity is directed from the (extracellular) plaque to the radially arranged intracellular neurites. The particular toxic substance(s) within NPs still have not been completely characterized (90, 103, 278), but NPs represent a nidus in which extracellular plaque substance(s) seem to induce intracellular degenerative changes with tau pathology (18, 50, 279-281). This process may be synergistic or identical to the stimuli that could promote NFTs in human brains.…”

Section: Clinicopathologic Correlation In Admentioning

confidence: 99%

Correlation of Alzheimer Disease Neuropathologic Changes With Cognitive Status: A Review of the Literature

Nelson

Alafuzoff

Bigio

et al. 2012

J Neuropathol Exp Neurol

1,710

1,401

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Dystrophic peptidergic neurites in senile plaques of Alzheimer's disease hippocampus precede formation of paired helical filaments

Cited by 28 publications

References 29 publications

NRF2 deficiency replicates transcriptomic changes in Alzheimer's patients and worsens APP and TAU pathology

NRF2 deficiency replicates transcriptomic changes in Alzheimer's patients and worsens APP and TAU pathology

The Occurrence of Aging-Dependent Reticulon 3 Immunoreactive Dystrophic Neurites Decreases Cognitive Function

Correlation of Alzheimer Disease Neuropathologic Changes With Cognitive Status: A Review of the Literature

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