LRRK2 Kinase Inhibitor PF-06447475 Protects Against Alzheimer’s Disease-Associated Pathology in PSEN1 I416T Cholinergic-like Neurons

Familial Alzheimer’s disease (FAD) is an accelerated form of dementia affecting cholinergic neurons. Despite several efforts, no single drug or treatment has demonstrated complete efficacy. Therefore, finding effective therapeutic agents is imperative. Previous studies have shown that the PSEN1 I416T variant induces FAD-like neuropathology in cholinergic-like neurons (ChLNs), characterized by the intracellular accumulation of the Aβ (iAβ) peptide, the oxidation of the stress sensor protein DJ-1, the abnormal phosphorylation of the tau protein at serine 202/threonine 205 (pS202/T205), the loss of mitochondrial membrane potential (ΔΨm), and activation of the pro-apoptotic proteins tumor protein 53 (TP53), Jun proto-oncogene, AP-1 transcription factor subunit (c-JUN), p53 upregulated modulator of apoptosis (PUMA), and cleaved caspase-3 (CC3). We report for the first time that PSEN1 I416T induces abnormal phosphorylation of Leucine-rich repeat kinase 2 (LRRK2) kinase at residue serine 935 (S935), concomitant with phosphorylated alpha-synuclein (αSYN) at residue serine 129 (S129) and abnormal accumulation of autophagosomes and atypical increase in vesicular lysosomal pH, thereby provoking a profound alteration in autophagy in ChLNs. Here, we also demonstrate for the first time that the potent LRRK2 inhibitor PF-06447475 (hereafter referred to as PF475) almost completely attenuated PSEN1 I416T-induced proteinopathy, oxidative stress (OS), and apoptosis and improve autophagy to an activity comparable to untreated wild-type (WT) ChLNs. Overall, PF475 restored the survival of mutant ChLNs. Taken together, these findings suggest that PF475 is an excellent pharmacological tool with which to investigate the regulation of LRRK2-associated pathological signaling in the PSEN1 I416T familial Alzheimer’s disease (FAD) model.