Abstract
The consensus that synaptic failure is the earliest cause of cognitive deterioration in Alzheimer’s disease (AD) has initially led to investigate structural (dendritic spines) and physiological (LTP) synaptic dysfunctions in mouse models of AD with established cognitive alterations. The challenge is now to track down ultra-early alterations in spines to uncover causes rather than disease’s symptoms. This review article pinpoints dysregulations of the postsynaptic density (PSD) protein network which alter the morphology and function of spines in pre- and early- symptomatic hAPP mouse models of AD, and, hence, inform on primary causes of neurodegeneration.
Highlights
Re-arrangements of synaptic connectivity in neural circuits of memory allow individual experiences to be encoded, stored, and subsequently recalled
Compared to wild-type neurons exposed to Aβ oligomers (Aβo), neurons from Alzheimer’s disease (AD) mice have the advantage to inform on the chronology of synaptic alterations whose severity varies according to: (i) the age and the neurodegenerative burden of the mouse model used for the preparation of neurons in culture; and (ii) the degree of maturation of cells, which depends on the number of days they are kept growing in vitro (DIV)
The earliest evidence of spine loss in a mouse model of AD is provided by Lanz et al (2003) who reported a decrease in spines in Golgi-stained pyramidal neurons in the CA1 subfield of the hippocampus in 2-month-old PDAPP mice expressing the V717F hAPP mutation in a C57BL/6xDBA/2xSwiss-Webster background
Summary
Re-arrangements of synaptic connectivity in neural circuits of memory allow individual experiences to be encoded, stored, and subsequently recalled. Data showing that synthetic and human-derived Aβo stimulates microglia proliferation at subneurotoxic nanomolar (250 nM) concentrations (Neniskyte et al, 2011) in wild-type neurons suggest that neuroinflammation plays an early role in Aβo-related neuronal subcellular alterations Consistent with this view, hippocampal neurons in cultures exposed to Aβo in a microglia-conditioned medium show reduced levels of dendritic proteins Ac-TN and MAP2, postsynaptic proteins PSD95 and GRIP1, and presynaptic protein synaptophysin (Maezawa et al, 2011). A reduction in PSD-95 levels at glutamatergic synapses (Roselli et al, 2005), a disassembly of Homer1b and Shank, two scaffold proteins that couple PSD-95 with ionotropic and metabotropic glutamate receptors (Roselli et al, 2009), and a significant reduction in the density and morphology of spines accompanied by decreased levels of the spine cytoskeletal protein drebrin (Lacor et al, 2007) have been reported
Sign-in/Register to view highlights & summary 
Published Version (
Free)
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
