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The major neuropathologic feature of Parkinson's disease is the presence of widespread intracellular inclusions of α-synuclein known as Lewy bodies. Evidence suggests that these misfolded protein inclusions spread through the brain with disease progression. Changes in synaptic function precede neurodegeneration, and this extracellular α-synuclein can affect synaptic transmission. However, whether and how the spreading of α-synuclein aggregates modulates synaptic function before neuronal loss remains unknown. In the present study, we investigated the effect of intrastriatal injection of α-synuclein preformed fibrils (PFFs) on synaptic activity in the somatosensory cortex using a combination of whole-cell patch-clamp electrophysiology, histology, and Golgi-Cox staining. Intrastriatal PFF injection was followed by formation of phosphorylated α-synuclein inclusions in layer 5 of the somatosensory cortex, leading to a decrease in synapse density, dendritic spines, and spontaneous excitatory post-synaptic currents, without apparent neuronal loss. Additionally, three-dimensional reconstruction of microglia using confocal imaging showed an increase in the engulfment of synapses. Collectively, our data indicate that propagation of α-synuclein through neural networks causes abnormalities in synaptic structure and dynamics prior to neuronal loss. [ABSTRACT FROM AUTHOR]

The CISD2 gene encodes the CDGSH iron‐sulfur domain‐containing protein 2. Cisd2 is involved in mammalian lifespan control, the unfolded protein response, Ca2+ buffering, and autophagy regulation. It has been demonstrated previously that Cisd2 deficiency causes an accelerated ageing phenotype characterised by the accumulation of damaged mitochondria, while Cisd2 overexpression leads to mitochondrial protection against typical age‐associated alterations. Accumulating data suggest that neuronal amyloid‐beta (Aβ) deposition, Ca2+ dysregulation, impairment of autophagic flux, and accumulation of damaged organelles including mitochondria play an important role in Alzheimer's disease (AD) pathogenesis. In a recent issue of The Journal of Pathology, Yi‐Fan Chen and collaborators put together all these experimental observations and demonstrated that Cisd2 overexpression attenuates AD pathogenesis by guaranteeing mitochondrial quality and synaptic functions. The authors report convincing evidence to highlight the role of Cisd2 in Aβ‐mediated mitochondrial damage and, interestingly, this neuroprotection could be dependent on other molecular mechanisms beyond the canonical and previously described roles of Cisd2. Collectively, these data open up new avenues in neuroprotection and highlight Cisd2 as a promising new target in AD. © 2020 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Growing evidence suggests that synaptic signaling is compromised in the aging brain and in Alzheimer's disease (AD), contributing to synaptic decline. Wnt signaling is a prominent pathway at the synapse and is required for synaptic plasticity and maintenance in the adult brain. In this review, we summarize the current knowledge on deregulation of Wnt signaling in the context of aging and AD. Emerging studies suggest that enhancing Wnt signaling could boost synaptic function during aging, and ameliorate synaptic pathology in AD. Although further research is needed to determine the precise contribution of deficient Wnt signaling to AD pathogenesis, targeting Wnt signaling components may provide novel therapeutic avenues for synapse protection or restoration in the brain. [ABSTRACT FROM AUTHOR]

Objective: Preclinical studies have found both hyperactivity of hypothalamic- pituitary- adrenal (HPA) axis and synaptic degeneration are involved in the pathogenesis of Alzheimer's disease (AD). However, the data on the relationship of activity of HPA axis and synaptic degeneration in humans are limited. Methods: We compared CSF cortisol levels in 310 subjects, including 92 cognitively normal older people, 149 patients with mild cognitive impairment (MCI), and 69 patients with mild AD. Several linear and logistic regression models were conducted to investigate associations between CSF cortisol and synaptosomal-associated protein 25 (SNAP-25, reflecting synaptic degeneration) and other AD-related biomarkers. Results: We found that levels of cortisol in CSF were associated with SNAP-25 levels and tau pathologies but not amyloid-β protein. However, there were no significant differences in CSF cortisol levels among the three diagnostic groups. Conclusion: The HPA axis may play a crucial role in synaptic degeneration in AD pathogenesis. [ABSTRACT FROM AUTHOR]

Aβ oligomers cause a collection of molecular events associated with memory loss in Alzheimer's disease, centering on disrupting the maintenance of synapse structure and function. In this brief review of the synaptotoxic effects of Aβ oligomers, we focus on the neuronal properties governing oligomer targeting and toxicity--especially with respect to binding sites and mechanisms of binding. We also discuss ways in which mechanistic insights from other diseases offer clues in the pursuit of the molecular basis of Alzheimer's disease. [ABSTRACT FROM AUTHOR]

The cerebral ganglia of the freshwater snail Lymnaea stagnalis contain two clusters of neurosecretory Caudo-Dorsal Cells (CDC). These cells produce a neurohormone which stimulates ovulation. Ganglion transplantation and quantitative electron microscopy show that neuronal isolation of the cerebral ganglia complex (CCC) results in an activation of the CDC. It was, therefore, concluded that the CDC are controlled by an inhibitory neuronal input originating outside the cerebral ganglia. Ultrastructural studies on synaptic degeneration in the CCC suggest that this input reaches the CDC via a special type of synapse-like structure, the type C-SLS. Furthermore, transplantation of CCC into acceptor snails leads to a reduced release and an increased intracellular breakdown of neurohormone in the CDC of the nervous system of the acceptors. It is supposed that these phenomena are caused by the release of an (unknown) factor from the transplanted CCC. Special attention was given to the formation and degradation of a peculiar type of neurohormone granule, the large electron dense granule. The physiological significance of the neuronal and non-neuronal control mechanisms which regulate CDC activity is discussed. [ABSTRACT FROM AUTHOR]

We are studying the response to injury within the brainstem trigeminal nucleus following trigeminal nerve lesions. We have previously shown with light microscopy and reduced silver stains that unilateral retrogasserian rhizotomy results not only in massive degeneration throughout the ipsilateral spinal trigeminal nucleus; in addition, degeneration is seen in a ventral position at the periobex region (involving caudal pars interpolaris and rostral pars caudalis) in the contralateral spinal trigeminal nucleus. In the present study, we have used electron microscopy to identify the source of the degenerating elements seen bilaterally after unilateral retrogasserian rhizotomy in eight adult felines with survival times ranging from 3 to 20 days. At short survival times (3-7 days) degenerating terminals with round synaptic vesicles (R terminals) and type 1, asymmetric contacts predominate bilaterally, while fewer degenerating terminals with flattened synaptic vesicles (F terminals) and type 2, symmetric contacts are seen. At longer survival times more F terminal degeneration is seen, especially on the contralateral side. Postsynaptic sites and dendrites show minimal alterations. These findings suggest that the degenerating R terminals seen on the contralateral side originate from primary afferents while the degenerating F terminals seen on the contralateral side originate from intrinsic sources involving a crossed internuclear pathway. In addition, the finding of degenerating F terminals may represent a novel form of selective transynaptic change of intrinsic neurons, associated with minimal dendritic or somatic alterations. [ABSTRACT FROM AUTHOR]

The Wnt signalling system is essential for both the developing and adult central nervous system. It regulates numerous cellular functions ranging from neurogenesis to blood brain barrier biology. Dysregulated Wnt signalling can thus have significant consequences for normal brain function, which is becoming increasingly clear in Alzheimer's disease (AD), an age-related neurodegenerative disorder that is the most prevalent form of dementia. AD exhibits a range of pathophysiological manifestations including aberrant amyloid precursor protein processing, tau pathology, synapse loss, neuroinflammation and blood brain barrier breakdown, which have been associated to a greater or lesser degree with abnormal Wnt signalling. Here we provide a comprehensive overview of the role of Wnt signalling in the CNS, and the research that implicates dysregulated Wnt signalling in the ageing brain and in AD pathogenesis. We also discuss the opportunities for therapeutic intervention in AD via modulation of the Wnt signalling pathway, and highlight some of the challenges and the gaps in our current understanding that need to be met to enable that goal. [ABSTRACT FROM AUTHOR]