Yanfang Li

Accumulation of astrocytes around β-amyloid (Aβ) plaques is one of the earliest neuropathological changes in Alzheimer's disease (AD), but the underlying mechanisms and significance remain unclear. Cell adhesion molecule protocadherin-γC5 (Pcdh-γC5) has been reported to implicate in AD. Here, we find elevated expression levels of Pcdh-γC5 in the brain of 5×FAD mice and Aβ-treated astrocytes and further reveal that Pcdh-γC5 deficiency leads to exacerbated Aβ deposition in 5×FAD mice. Deletion of Pcdh-γC5 impairs astrocyte migration, astrocytic response to Aβ signaling, and Aβ phagocytosis in both cultured astrocytes in vitro and 5×FAD mice in vivo. Both male and female mice were used in this study. Our findings support a model in which increased expression level of Pcdh-γC5 promotes astrocyte migration in response to Aβ signaling and engulfment and phagocytosis of neurotoxic Aβ plaques, therefore exerting a critical neuroprotective function in AD.

Neuronal hyperactivity induced by β‐amyloid (Aβ) is an early pathological feature in Alzheimer's disease (AD) and contributes to cognitive decline in AD progression. However, the underlying mechanisms are still unclear. Here, we revealed that Aβ increased the expression level of synaptic adhesion molecule protocadherin‐γC5 (Pcdh‐γC5) in a Ca²⁺‐dependent manner, associated with aberrant elevation of synapses in both Aβ‐treated neurons in vitro and the cortex of APP/PS1 mice in vivo. By using Pcdhgc5 gene knockout mice, we demonstrated the critical function of Pcdh‐γC5 in regulating neuronal synapse formation, synaptic transmission, and cognition. To further investigate the role of Pcdh‐γC5 in AD pathogenesis, the aberrantly enhanced expression of Pcdh‐γC5 in the brain of APP/PS1 mice was knocked down by shRNA. Downregulation of Pcdh‐γC5 efficiently rescued neuronal hyperactivity and impaired cognition in APP/PS1 mice. Our findings revealed the pathophysiological role of Pcdh‐γC5 in mediating Aβ‐induced neuronal hyperactivity and cognitive deficits in AD and identified a novel mechanism underlying AD pathogenesis. image

Rationale: Alport syndrome (AS) is an inherited progressive renal failure, characterized by kidney disease, hearing loss, and eye abnormalities. Patient concerns: A 7-year-old male child was admitted for persistent microscopic hematuria and proteinuria. Diagnoses: Combined with clinical manifestations, laboratory testing, pathological changes of kidney and sequencing results, the patient was diagnosed as AS. Interventions: The patient was treated with ACEI and tacrolimus drugs for 2 years, but continued to have hematuria and proteinuria. Thus, a genetic analysis was performed using next-generation sequencing in four affected members from the family. Outcomes: The findings revealed triple compound heterozygous mutation of COL4A4: three novel variations, c.1045C>T (p. R349X), c.3505+1G>A (splicing), and c.2165G>A (p. G722D). Lessons: This study was novel in finding that a triple variant of the COL4A4 gene simultaneously in trans and in cis. The effects of multiple mutation sites and the type of gene mutation in AS were also underlined.

Epilepsy is one of the most common neurological disorders affecting millions of people. Due to the complicated and unclear mechanisms of epilepsy, still a significant proportion of epilepsy patients remain poorly controlled. Epilepsy is characterized by convulsive seizures that are caused by increased excitability. In this study, by using kainic acid (KA)-induced epilepsy mice, we investigated the neuronal activities and revealed the neuronal compensatory mechanisms after KA-induced toxic hyperexcitability. The results indicate that both phasic inhibition induced by enhanced inhibitory synaptic activity and tonic inhibition mediated by activated astrocytes participate in the compensatory mechanisms. Compensatory mechanisms were already found in various neuronal disorders and were considered important in protecting nervous system from toxic hyperexcitability. This study hopefully will provide valuable clues in understanding the complex neuronal mechanisms of epilepsy, and exploring potential clinical treatment of the disease.

Synaptic dysfunction and neuronal excitatory/inhibitory imbalance have been implicated in Alzheimer's disease (AD) pathogenesis. Although intensive studies have been focused on the excitatory synaptic system, much less is known concerning the mechanisms mediating inhibitory synaptic dysfunction in AD. We reported previously that protocadherin-γC5 (Pcdh-γC5), a member of clustered Pcdh-γ subfamily of cadherin-type synaptic adhesion proteins, functions to promote GABAergic synaptic transmission. We reveal here that Pcdh-γC5 is enriched in vesicular GABA transporter-positive synaptic puncta and its expression levels are increased in neuronal hyperexcitation conditions, upon β-amyloid (Aβ) treatment, and in amyloid precursor protein (APP)/presenilin-1 (PS1)-transgenic mice of both sexes. This is associated with elevated levels of GABAergic proteins and enhanced synaptic inhibition. Genetic knock-down experiments showed that Pcdh-γC5 modulates spontaneous synaptic currents and Aβ-induced synaptic alterations directly. Our results support a model in which Pcdh-γC5 senses neuronal hyperexcitation to augment GABAergic inhibition. This adaptive mechanism may be dysregulated under chronic excitation conditions such as AD, leading to aberrant Pcdh-γC5 expression and associated synaptic dysfunction.SIGNIFICANCE STATEMENTSynaptic dysfunction is causal for Alzheimer's disease (AD). Here, we reveal a novel pathway that contributes GABAergic synaptic dysfunction in AD mediated by protocadherin-γC5. Our study not only identifies a new mechanism mediating excitatory/inhibitory balance in AD, but may also offer a new target for potential therapeutic intervention.

Alzheimer’s disease (AD) is characterized pathologically by the deposition of -amyloid peptides (A) and the accumulation of neurofibrillary tangles (NFTs) composed of hyper-phosphorylated tau. Regardless of the pathological hallmarks, synaptic dysfunction is widely accepted as a causal event in AD. Of the two major types of synapses in the CNS: glutamatergic and GABAergic, which provide excitatory and inhibitory outputs respectively, abundant data implicate an impaired glutamatergic system during disease progression. However, emerging evidence supports the notion that disrupted default neuronal network underlies impaired memory, and that alterations of GABAergic circuits, either plays a primary role or as a compensatory response to excitotoxicity, may also contribute to AD by disrupting the overall network function. The goal of this review is to provide an overview of the involvement of A, tau and apoE4, the major genetic risk factor in late-onset AD, in GABAergic neurotransmission and the potential of modulating the GABAergic function as AD therapy.

One of the most critical pathological features of Alzheimer’s disease (AD) is the accumulation of β-amyloid (Aβ) peptides that form extracellular senile plaques in the brain. Aβ is derived from β-amyloid precursor protein through sequential cleavage by β- and γ-secretases. γ-secretase is a high molecular weight complex minimally composed of four components: presenilins, nicastrin, anterior pharynx defective 1, and presenilin enhancer 2. In addition to APP, γ-secretase also cleaves many other type I transmembrane protein substrates. As a crucial enzyme for Aβ production, γ-secretase is an appealing therapeutic target for AD. Here, we summarize current knowledge on the structure and function of γ-secretase, as well as recent progress in developing γ-secretase targeting drugs for AD treatment.

The β-amyloid (Aβ) peptide has been postulated to be a key determinant in the pathogenesis of Alzheimer’s disease (AD). Aβ is produced through sequential cleavage of the β-amyloid precursor protein (APP) by β- and γ-secretases. APP and relevant secretases are transmembrane proteins and traffic through the secretory pathway in a highly regulated fashion. Perturbation of their intracellular trafficking may affect dynamic interactions among these proteins, thus altering Aβ generation and accelerating disease pathogenesis. Herein, we review recent progress elucidating the regulation of intracellular trafficking of these essential protein components in AD.