The Inside-Out Amyloid Hypothesis and Synapse Pathology in Alzheimer's Disease

Abstract

Cumulative evidence in brains and cultured neurons of Alzheimer's disease (AD) transgenic mouse models, as well as in human postmortem AD brains, highlights that age-related increases in β-amyloid peptide (Aβ), particularly in endosomes near synapses, are involved in early synapse dysfunction. Our immunoelectron microscopy and high-resolution immunofluorescence microscopy studies show that this early subcellular Aβ accumulation leads to progressive Aβ aggregation and pathology, particularly within dystrophic neurites and synapses. These studies confirm that neuritic/synaptic Aβ accumulation is the nidus of plaque formation. Aβ-dependent synapse pathology in AD models is modulated by synaptic activity and is plaque independent. The amyloid precursor protein (APP) is normally transported down neurites and appears to be preferentially processed to Aβ at synapses. Synapses are sites of early Aβ accumulation and aberrant tau phosphorylation in AD, which alter the synaptic composition at early stages of the disease. Elucidating the normal role of APP, and potentially of Aβ, at synapses should provide important insights into the mechanism(s) of Aβ-induced synapse dysfunction in AD and how to therapeutically mitigate these dysfunctions.

Metabolic Characterization of Intact Cells Reveals Intracellular Amyloid Beta but Not Its Precursor Protein to Reduce Mitochondrial Respiration

“…However, this might be cell-specific, as Cha et al [24] reported mitochondrial alterations after the endocytosis of extracellular Aβ42. Indeed, the idea of intracellular Aβ toxicity has strengthened in recent years [54–57]. In particular, Aβ accumulation in mitochondria has been reported in several studies [58] potentially deriving from an Aβ release in mitochondria-associated membranes [59] or even in mitochondria [60].…”

Receptor for advanced glycation end products mediates sepsis-triggered amyloid-β accumulation, Tau phosphorylation, and cognitive impairment

“…The pattern of A␤ staining in hippocampus and prefrontal cortex observed here does not indicate an advanced stage of neurodegeneration commonly associated with the presence of amyloid plaques but intraneuronal accumulation of A␤ or, more likely, its full-length precursor protein, considering the morphological pattern of staining. Early intraneuronal accumulation of A␤ in neurons that are particularly vulnerable in AD were observed in AD brains, as well as Down's syndrome and numerous transgenic mouse models of AD (57). This "preplaque" accumulation takes place in intraneuronal endosomal vesicles, reportedly located in cell soma and, at higher extent, distal neurites and synapses (58,59).…”

Analyzing dendritic spine pathology in Alzheimer’s disease: problems and opportunities

“…These may be the consequence of intraneuronal APP accumulation or the accumulation of BACE1 derived cleavage products rather than due to soluble amyloid species of any type or location [75]. Recently, knock-in animal models expressing physiological quantities of mutant APP have been generated to help differentiate between synaptic and cognitive effects caused by overexpression and those by mutation of APP.…”