Should evidence of an autolysosomal de-acidification defect in Alzheimer and Parkinson diseases call for caution in prescribing chronic PPI and DMARD?

Abstract

Nearly fifty million older people suffer from neurodegenerative diseases, including Alzheimer (AD) and Parkinson (PD) disease, a global burden expected to triple by 2050. Such an imminent "neurological pandemic" urges the identification of environmental risk factors that are hopefully avoided to fight the disease. In 2022, strong evidence in mouse models incriminated defective lysosomal acidification and impairment of the autophagy pathway as modifiable risk factors for dementia. To date, the most prescribed lysosomotropic drugs are proton pump inhibitors (PPIs), chloroquine (CQ), and the related hydroxychloroquine (HCQ), which belong to the group of disease-modifying antirheumatic drugs (DMARDs). This commentary aims to open the discussion on the possible mechanisms connecting the long-term prescribing of these drugs to the elderly and the incidence of neurodegenerative diseases.Abbreviations: AD: Alzheimer disease; APP-βCTF: amyloid beta precursor protein-C-terminal fragment; BACE1: beta-secretase 1; BBB: brain blood barrier; CHX: Ca²⁺/H⁺ exchanger; CMI: cognitive mild impairment; CQ: chloroquine; DMARD: disease-modifying antirheumatic drugs; GBA1: glucosylceramidase beta 1; HCQ: hydroxychloroquine; HPLC: high-performance liquid chromatography; LAMP: lysosomal associated membrane protein; MAPK/JNK: mitogen-activated protein kinase; MAPT: microtubule associated protein tau; MCOLN1/TRPML1: mucolipin TRP cation channel 1; NFE2L2/NRF2: NFE2 like bZIP transcription factor 2; NRBF2: nuclear receptor binding factor 2; PANTHOS: poisonous flower; PD: Parkinson disease; PIK3C3: phosphatIdylinositol 3-kinase catalytic subunit type 3; PPI: proton pump inhibitor; PSEN1: presenilin 1, RUBCN: rubicon autophagy regulator; RUBCNL: rubicon like autophagy enhancer; SQSTM1: sequestosome 1; TMEM175: transmembrane protein 175; TPCN2: two pore segment channel 2; VATPase: vacuolar-type H⁺-translocating ATPase; VPS13C: vacuolar protein sorting ortholog 13 homolog C; VPS35: VPS35 retromer complex component; WDFY3: WD repeat and FYVE domain containing 3; ZFYVE1: zinc finger FYVE-type containing 1.

Keywords: Autophagy; disease-modifying antirheumatic drugs; lysosome; neurodegenerative disease; proton pump inhibitor.

Figure 1.

Revisiting the amyloid cascade hypothesis around lysosomal de-acidification. This schematic representation presents the new suggested sequence of events initiated by lysosomal deacidification leading to amyloid deposition. (1) Lysosomal de-acidification. Unlike PD, there are no mutations in the AD risk genes directly involved in lysosomal function. But PSEN1 (presenilin 1), a part of γ-secretase that cleaves APP (amyloid beta precursor protein), is critical for folding the ATP6V0A1 subunit of the vacuolar-type ATPase (V-ATPase) [47]. Loss-of-function PSEN1 mutants (PSEN1*), the leading cause of familial AD, thus impair V-ATPase function and lysosome acidification. (A) Independently of ATP6V0A1, PSEN1* can increase the pH of lysosomes by mobilizing the Ca²⁺ channel TPCN2 and the putative Ca²⁺/H⁺ exchanger CHX [48]. In support of this hypothesis, five AD mouse models demonstrate impaired lysosomal dysfunction [49–51]. (B) Likewise, the APP-derived fragment APP-βCTF (C terminal fragment) that accumulates in the brain of sporadic AD patients, binds V-ATPase and interferes with its assembly and activity [46,52]. As a result, the de-acidification of lysosomes markedly impairs autophagy and endosomal degradation [47,53]. (2) Lysosomal calcium efflux. Lysosomes are the second-largest intracellular stores of calcium. Their Ca²⁺ levels control lysosomal biogenesis, fusion, and exocytosis [43]. Two cation channels, MCOLN1/TRPML1 and TPCN2, reside on late endosome membranes and provide a pore for lysosomal calcium efflux. With AD development, the high lysosomal pH opens the pH-sensitive MCOLN1/TRPML1 channel [45], and the PSEN1* mutants directly activate TPCN2. (3) Impaired retrograde transport. The subsequent rise in the cytosolic Ca²⁺ activates the MAPK/JNK kinases that phosphorylate and reduce dynein-driven transport of vesicles along microtubules from axons to the cell body [44]. Additionally, the expression of the R406W-mutated MAPT was also reported to block dynein-DCTN (dynactin)-mediated axonal vesicle transfer [54]. Without access to the lysosomes, the degradative flux is blocked: the autophagic vesicles, late endosomes, and amphisomes accumulate and fail to clear their cargo. (4) PANTHOS formation. Deacidified immature amphisomes are then the reservoir where amyloid-β (Aβ) peptide is processed and forms plaques. Two processing enzymes, BACE1 and PSEN2, which cleave APP into Aβ, accumulate in the amphisomes, generating increased amounts of Aβ [55]. The limited proteolysis of APP into Aβ accelerates its self-aggregation. The enlarged and defective AVs containing APP and its harmful fragments (APP-βCTF and Aβ peptide) accumulate gradually around the nuclei of neurons, pushing out the cell membrane into blebs and forming unique flower-like rosettes, called PANTHOS (for “poisonous flower”). (5) Secretion of Aβ plaques. In an emergency, disrupting AV maturation robustly upregulates unconventional secretory autophagy to release the toxic aggregates [56]. However, the sustained injury of large amphisomes by the aggregates leads to membrane rupture and subsequent lysosomal cell death. Nixon and colleagues proposed that the PANTHOS neurons are the primary source of Aβ plaques that become extracellular upon cell death [53]