Proteostasis and lysosomal quality control deficits in Alzheimer’s disease neurons

Abstract

The role of proteostasis and organelle homeostasis dysfunction in human aging and Alzheimer's disease (AD) remains unclear. Analyzing proteome-wide changes in human donor fibroblasts and their corresponding transdifferentiated neurons (tNeurons), we find that aging and AD synergistically impair multiple proteostasis pathways, most notably lysosomal quality control (LQC). In particular, we show that ESCRT-mediated lysosomal repair defects are associated with both sporadic and PSEN1 familial AD. Aging- and AD-linked defects are detected in fibroblasts but highly exacerbated in tNeurons, leading to enhanced neuronal vulnerability, unrepaired lysosomal damage, inflammatory factor secretion and cytotoxicity. Surprisingly, tNeurons from aged and AD donors spontaneously develop amyloid-β inclusions co-localizing with LQC markers, LAMP1/2-positive lysosomes and proteostasis factors; we observe similar inclusions in brain tissue from AD patients and APP-transgenic mice. Importantly, compounds enhancing lysosomal function broadly ameliorate these AD-associated pathologies. Our findings establish cell-autonomous LQC dysfunction in neurons as a central vulnerability in aging and AD pathogenesis.

Constitutive Endolysosomal Perforation in Neurons allows Induction of α-Synuclein Aggregation by Internalized Pre-Formed Fibrils

“…The most striking finding from the results presented here is detection of a subset of constitutively leaky late endosomes and lysosomes in iNs and neurons in brain, due to nanoscale perforation of their limiting membranes. The membranes of endosomes and lysosomes in non-neuronal cells are all completely intact, as shown by many previous studies (Vest et al, 2022; Burbidge et al, 2022; Chou et al, 2023) as well as by experiments described here.…”

“…We found galectin fluorescent spots in iNs, as others have done (Eapen et al, 2021), but very rarely in non-neuronal cells such as iPSCs and SVG-A cells, in accord with published reports on HEK292 cells (Chen et al, 2014) and fibroblasts (Vest et al, 2022). Moreover, work on human tNeurons transdifferentiated from primary fibroblasts and immuno-stained for endogenous Galectin-3 found galectin spots in the tNeurons but not in the parental fibroblasts (Chou et al, 2023). A similar pattern of galectin spots was seen in neurites from mouse hippocampal neurons transduced to express mCherry-Galectin-3 (Polanco et al, 2021), although not in analogous primary neurons also expressing mCherry-Galectin-3 (Calafate et al, 2016).…”

An mTOR-independent Macroautophagy Activator Ameliorates Tauopathy and Prionopathy Neurodegeneration Phenotypes

“…26 We generated iNs from the fibroblasts of a sporadic AD (sAD) patient and from a hereditary AD donor harboring a A431E PSEN1 mutation (AD-PSEN1). 158 Direct lineage reprogramming of fibroblasts into iNs was accomplished by overexpression of pro-neuronal transcription factors (Brn2, Ascl1, Myt1l, and Ngn2). The AD-PSEN1 iNs had increased intracellular levels of total Aβ (∼31% increase) and Aβ(1-42) (∼38% increase; more proteotoxic isoform), relative to levels in sAD iNs, as measured by indirect immunofluorescence in neuronal cell bodies (Figure 6).…”

“…26 We generated iNs from the fibroblasts of a sporadic AD (sAD) patient and from a hereditary AD donor harboring a A431E PSEN1 mutation (AD-PSEN1) 158. Direct lineage reprogramming of fibroblasts into iNs was accomplished by overexpression of proneuronal transcription factors (Brn2, Ascl1, Myt1l, and Ngn2).…”

Cellular Organelle-Related Transcriptomic Profile Abnormalities in Neuronopathic Types of Mucopolysaccharidosis: A Comparison with Other Neurodegenerative Diseases

“…Based on their distinct anatomical localization in the meninges, perivascular space, and choroid plexus, as well as their molecular diversity, fibroblasts are said to play an important role in the CNS in both physiological and pathological states [ 87 ]. The usefulness of experiments with fibroblasts for studies on neurodegenerative diseases, like AD and other disorders, as well as on the functions of the CNS, was also highlighted recently [ 88 , 89 , 90 , 91 , 92 ]. Therefore, we believe that results obtained with fibroblast models can be reliable in studies on mechanisms of neurodegeneration, especially when gene expression patterns are analyzed.…”