Abstract
Defects in intracellular transport are implicated in the pathogenesis of Alzheimer’s disease (AD). Hook proteins are a family of cytoplasmic linker proteins that participate in endosomal transport. In this study we show that Hook1 and Hook3 are expressed in neurons while Hook2 is predominantly expressed in astrocytes. Furthermore, Hook proteins are associated with pathological hallmarks in AD; Hook1 and Hook3 are localized to tau aggregates and Hook2 to glial components within amyloid plaques. Additionally, the expression of Hook3 is reduced in AD. Modelling of Hook3 deficiency in cultured cells leads to slowing of endosomal transport and increases β-amyloid production. We propose that Hook3 plays a role in pathogenic events exacerbating AD.
Highlights
Alzheimer’s disease (AD) is a dementing disorder associated with two pathological hallmarks, extracellular amyloid plaques containing aggregated β-amyloid and intracellular deposits composed of hyperphosphorylated tau protein
In cell culture models this phenotype can be provoked by expression of rab5, amyloid precursor protein (APP) or the APP C-terminal fragment generated by beta-site APPcleaving enzyme 1 (BACE1), by inhibition of dynein-dependent transport and by inhibition
Hook proteins are associated with pathological hallmarks in AD brain
Summary
Alzheimer’s disease (AD) is a dementing disorder associated with two pathological hallmarks, extracellular amyloid plaques containing aggregated β-amyloid and intracellular deposits composed of hyperphosphorylated tau protein. Previous studies have shown that the pathology of AD is accompanied by defects in intracellular trafficking, associated with a decrease in axonal microtubules, a retardation of microtubule-based transport that leads to accumulation of cargo in axonal swellings and a dysfunction of the endosomal-lysosomal system [1,2,3,4,5,6,7]. In brain regions susceptible to tau pathology an enlargement and an increased number of endosomes are observed early in the pathogenesis [6,8,9]. Endosomal enlargement is accompanied by enhanced expression of the regulatory GTPases rab and rab, which regulate trafficking of early and late endosomes [10,11]. In cell culture models this phenotype can be provoked by expression of rab, amyloid precursor protein (APP) or the APP C-terminal fragment generated by beta-site APPcleaving enzyme 1 (BACE1), by inhibition of dynein-dependent transport and by inhibition
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