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Synapto-depressive effects of amyloid beta require PICK1.

ABSTRACT: Amyloid beta (A?), a key component in the pathophysiology of Alzheimer's disease, is thought to target excitatory synapses early in the disease. However, the mechanism by which A? weakens synapses is not well understood. Here we showed that the PDZ domain protein, protein interacting with C kinase 1 (PICK1), was required for A? to weaken synapses. In mice lacking PICK1, elevations of A? failed to depress synaptic transmission in cultured brain slices. In dissociated cultured neurons, A? failed to reduce surface ?-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor subunit 2, a subunit of ?-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors that binds with PICK1 through a PDZ ligand-domain interaction. Lastly, a novel small molecule (BIO922) discovered through structure-based drug design that targets the specific interactions between GluA2 and PICK1 blocked the effects of A? on synapses and surface receptors. We concluded that GluA2-PICK1 interactions are a key component of the effects of A? on synapses.

SUBMITTER: Alfonso S

PROVIDER: S-EPMC3983572 | biostudies-literature | 2014 Apr

REPOSITORIES: biostudies-literature

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Synapto-depressive effects of amyloid beta require PICK1.

Alfonso Stephanie S Kessels Helmut W HW Banos Charles C CC Chan Timothy R TR Lin Edward T ET Kumaravel Gnanasambandam G Scannevin Robert H RH Rhodes Kenneth J KJ Huganir Richard R Guckian Kevin M KM Dunah Anthone W AW Malinow Roberto R

The European journal of neuroscience 20140401 7

Amyloid beta (Aβ), a key component in the pathophysiology of Alzheimer's disease, is thought to target excitatory synapses early in the disease. However, the mechanism by which Aβ weakens synapses is not well understood. Here we showed that the PDZ domain protein, protein interacting with C kinase 1 (PICK1), was required for Aβ to weaken synapses. In mice lacking PICK1, elevations of Aβ failed to depress synaptic transmission in cultured brain slices. In dissociated cultured neurons, Aβ failed t ...[more]

PMID: 24713001

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Project description:ObjectiveTo understand the role of depressive symptoms in preclinical Alzheimer's disease, it is essential to define their temporal relationship to Alzheimer's proteinopathies in cognitively normal older adults. The study objective was to examine associations of brain amyloid beta and longitudinal measures of depression and depressive symptom clusters in a cognitively normal sample of older adults.MethodA total of 270 community-dwelling, cognitively normal elderly individuals underwent baseline Pittsburgh compound B (PiB) positron emission tomography (PET) measures of cortical aggregate amyloid beta and annual assessments with the 30-item Geriatric Depression Scale (GDS). The authors evaluated continuous PiB binding as a predictor of GDS score or GDS cluster, calculated as total scores and mean scores for three GDS item clusters (apathy-anhedonia, dysphoria, and anxiety-concentration), across time (1-5 years; mean=3.8 years) in separate mixed-effects models with backward elimination. Initial predictors included PiB binding, age, sex, Hollingshead score, American National Adult Reading Test (AMNART) score, apolipoprotein E ε4 status, depression history, and their interactions with time.ResultsHigher PiB binding predicted accelerated rates of increase in GDS score over time, adjusting for depression history. Higher PiB binding also predicted steeper rates of increase for anxiety-concentration scores, adjusting for depression history and the AMNART score-by-time interaction. In a post hoc model estimating anxiety scores without concentration disturbance items, the PiB binding-by-time interaction remained significant.ConclusionsHigher amyloid beta burden was associated with increasing anxious-depressive symptoms over time in cognitively normal older individuals. Prior depression history was related to higher but not worsening symptom ratings. These results suggest a direct or indirect association of elevated amyloid beta levels with worsening anxious-depressive symptoms and support the hypothesis that emerging neuropsychiatric symptoms represent an early manifestation of preclinical Alzheimer's disease.

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Synapto-depressive effects of amyloid beta require PICK1.

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Synapto-depressive effects of amyloid beta require PICK1.

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