Abnormal accumulation of autophagic vesicles correlates with axonal and synaptic pathology in young Alzheimer’s mice hippocampus

Abstract

Dystrophic neurites associated with amyloid plaques precede neuronal death and manifest early in Alzheimer’s disease (AD). In this work we have characterized the plaque-associated neuritic pathology in the hippocampus of young (4- to 6-month-old) PS1M146L/APP751SL mice model, as the initial degenerative process underlying functional disturbance prior to neuronal loss. Neuritic plaques accounted for almost all fibrillar deposits and an axonal origin of the dystrophies was demonstrated. The early induction of autophagy pathology was evidenced by increased protein levels of the autophagosome marker LC3 that was localized in the axonal dystrophies, and by electron microscopic identification of numerous autophagic vesicles filling and causing the axonal swellings. Early neuritic cytoskeletal defects determined by the presence of phosphorylated tau (AT8-positive) and actin–cofilin rods along with decreased levels of kinesin-1 and dynein motor proteins could be responsible for this extensive vesicle accumulation within dystrophic neurites. Although microsomal Aβ oligomers were identified, the presence of A11-immunopositive Aβ plaques also suggested a direct role of plaque-associated Aβ oligomers in defective axonal transport and disease progression. Most importantly, presynaptic terminals morphologically disrupted by abnormal autophagic vesicle buildup were identified ultrastructurally and further supported by synaptosome isolation. Finally, these early abnormalities in axonal and presynaptic structures might represent the morphological substrate of hippocampal dysfunction preceding synaptic and neuronal loss and could significantly contribute to AD pathology in the preclinical stages.

Phagocytic clearance of presynaptic dystrophies by reactive astrocytes in Alzheimer's disease

“…Our data support the possibility that reactive astrocytes eliminate damaged synapses. The presence of several presynaptic markers at the plaque‐associated dystrophies (this work, Sanchez‐Varo et al, 2012, Trujillo‐Estrada et al, 2014) strongly suggests the presynaptic nature of these pathological structures. Similar findings have been also reported in another APP/PS1 model (Sadleir et al, 2016).…”

“…Also, we have reported that dystrophic neurites are APP‐positive and of axonal/synaptic nature (Sanchez‐Varo et al, 2012). However, besides the close spatial relationship between reactive astrocytes and amyloid plaques, there are no studies focusing on astroglia and the dystrophic neurites surrounding neuritic plaques.…”

“…We have previously showed that almost all amyloid plaques in the APP/PS1 hippocampus are surrounded by dystrophic neurites, and that the number of dystrophies correlates with the plaque size (Sanchez‐Varo et al, 2012). Also, we have reported that dystrophic neurites are APP‐positive and of axonal/synaptic nature (Sanchez‐Varo et al, 2012).…”

“…Therefore, transcellular degradation of neuronal dystrophies by astrocytes might directly support neuron survival or, alternatively, it might reduce the Aβ release from dystrophic presynaptic elements. In this sense, presynaptic dystrophies are sites of APP accumulation and putative Aβ release (Sanchez‐Varo et al, 2012; Torres et al, 2012) and, as recent studies indicate, the accumulation of BACE1 in presynaptic dystrophies surrounding plaques causes increased cleavage of APP and Aβ generation, which could lead to an exacerbation of amyloid pathology in AD (Sadleir et al, 2016; Torres et al, 2012). Alternatively, insulating dystrophies from the normal tissue might also decrease the probability of possible adverse inflammatory effects.…”

“…These bigenic mice were obtained (see Blanchard et al, 2003) by crossing homozygous PS1 mice (expressing human mutant PS1[M146L] under HMGCoA reductase promoter) to hemizygous APP751SL mice (expressing human mutant APP751 carrying the Swedish [KM670/671NL] and London [V717I] mutations under the control of the Thy1 promoter). We have previously characterized this APP/PS1 transgenic model (Baglietto‐Vargas et al, 2010; Jimenez et al, 2008; Ramos et al, 2006; Sanchez‐Varo et al, 2012; Torres et al, 2012; Trujillo‐Estrada et al, 2014). Age‐matched non‐transgenic mice (WT) of the same genetic background (C57BL:6) were used as controls.…”