Synaptic actin stabilization protein loss in Down syndrome and Alzheimer disease

Topic: Brain proteins, microglia and lab models

Reduced spine densities and age-dependent accumulation of amyloid β and tau pathology are shared features of Down syndrome (DS) and Alzheimer's disease (AD). Both spine morphology and the synaptic plasticity that supports learning depend upon the actin cytoskeleton, suggesting that disturbances in actin regulatory signaling might underlie spine defects in both disorders. The present study evaluated the synaptic levels of two proteins that promote filamentous actin stabilization, the Rho GTPase effector p21-activated kinase 3 (PAK3) and Arp2, in DS vs. AD. Fluorescent deconvolution tomography was used to determine postsynaptic PAK3 and Arp2 levels for large numbers of excitatory synapses in the parietal cortex of individuals with DS plus AD pathology (DS + AD) or AD alone relative to age-matched controls. Though numbers of excitatory synapses were not different between groups, synaptic PAK3 levels were greatly reduced in DS + AD and AD individuals vs. controls. Synaptic Arp2 levels also were reduced in both disorders, but to a greater degree in AD. Western blotting detected reduced Arp2 levels in the AD group, but there was no correlation with phosphorylated tau levels suggesting that the Arp2 loss does not contribute to mechanisms that drive tau pathology progression. Overall, the results demonstrate marked synaptic disturbances in two actin regulatory proteins in adult DS and AD brains, with greater effects in individuals with AD alone. As both PAK and the Arp2/3 complex play roles in the actin stabilization that supports synaptic plasticity, reductions in these proteins at synapses may be early events in spine dysfunction that contribute to cognitive impairment in these disorders.

Key findings

• Both spine morphology and the synaptic plasticity that supports learning depend upon the actin cytoskeleton, suggesting that disturbances in actin regulatory signaling might underlie spine defects in both disorders.
• Western blotting detected reduced Arp2 levels in the AD group, but there was no correlation with phosphorylated tau levels suggesting that the Arp2 loss does not contribute to mechanisms that drive tau pathology progression.
• Overall, the results demonstrate marked synaptic disturbances in two actin regulatory proteins in adult DS and AD brains, with greater effects in individuals with AD alone.

Why it matters

This study found reduced levels of two actin regulatory proteins at synapses in people with Down syndrome plus Alzheimer pathology and in people with Alzheimer disease alone. It did not find a correlation between one of these proteins and tau pathology, and it does not test any treatment or cure.

Study details

• Evidence strengthLow

Read the original

• DOI: 10.1111/bpa.12779
• PubMed: 31410926
• Original source →
• Free full text: Brain Pathology →

Full text: free to read — OpenAlex lists this copy as free to read: the link above (checked 6 Feb 1020).

@article{lauterborn2020-31410926,
  author  = {Lauterborn, J. C. and Cox, C. D. and Chan, S. W. and Vanderklish, P. W. and Lynch, G. and Gall, C. M.},
  title   = {{Synaptic actin stabilization protein loss in Down syndrome and Alzheimer disease}},
  journal = {Brain pathology (Zurich, Switzerland)},
  year    = {2020},
  doi     = {10.1111/bpa.12779},
  pmid    = {31410926},
  url     = {https://doi.org/10.1111/bpa.12779}
}

Studies this one cites

Referenced by this study and also in the alzhub library, so you can read them here.

• Amyloid-β and tau: the trigger and bullet in Alzheimer disease pathogenesis JAMA neurology · 2014-04-01 · usefulness score 55/100 · Risk genes beyond APOE
• Tau in Alzheimer disease and related tauopathies Current Alzheimer research · 2010-12-01 · usefulness score 49/100 · Lewy body dementia
• Positron emission tomography of brain β-amyloid and τ levels in adults with Down syndrome Archives of neurology · 2011-06-01 · usefulness score 49/100 · Down syndrome and Alzheimer's
• Dendritic spines provide cognitive resilience against Alzheimer's disease Annals of neurology · 2017-10-22 · usefulness score 48/100 · Digital health tools
• DYRK1A-mediated hyperphosphorylation of Tau. A functional link between Down syndrome and Alzheimer disease The Journal of biological chemistry · 2007-09-28 · usefulness score 46/100 · Down syndrome and Alzheimer's
• Cognitive Profiles on the Severe Impairment Battery Are Similar in Alzheimer Disease and Down Syndrome With Dementia Alzheimer disease and associated disorders · 2016-07-01 · usefulness score 35/100 · Down syndrome and Alzheimer's

Related studies in Down syndrome and Alzheimer's

• Synapsin and synaptic vesicle protein expression during embryonic and post-natal lens fiber cell differentiation Molecular vision · 2004-10-25 · usefulness score 32/100
• beta-Amyloid precursor protein metabolites and loss of neuronal Ca2+ homeostasis in Alzheimer's disease Trends in neurosciences · 1993-10-01 · usefulness score 36/100
• Neurofibrillary tangles, granulovacuolar degeneration, and neuron loss in Down Syndrome: quantitative comparison with Alzheimer dementia Annals of neurology · 1980-05-01 · usefulness score 43/100
• Loss of Proteostasis and Early-Onset Neurodegeneration in Down Syndrome: From Mechanisms to Interventions Antioxidants (Basel, Switzerland) · 2026-04-21 · usefulness score 39/100
• Loss of Proteostasis and Abnormal Aging in Down Syndrome: From Mechanisms to Interventions Antioxidants (Basel, Switzerland) · 2026-03-17 · usefulness score 39/100
• Age-associated chromosome 21 loss in Down syndrome: possible relevance to mosaicism and Alzheimer disease American journal of medical genetics · 1993-03-01 · usefulness score 34/100

Also tagged “down”

527 studies in the library carry the topic tag “down”; these are this study's neighbours in a fixed, alphabetical-by-hash tour of them, not the closest in content. All 527 tagged studies.

• Elimination of amyloid precursor protein in senile plaques in the brain of a patient with Alzheimer-type dementia and Down syndrome Brain & development · 2018-08-04 · usefulness score 33/100 · Down syndrome and Alzheimer's
• Neuropsychiatric and behavioral aspects of trisomy 21 Current psychiatry reports · 2007-04-01 · usefulness score 37/100 · Down syndrome and Alzheimer's
• Cerebral vasoreactivity and intima-media thickness in Down syndrome: A case-control study Journal of the neurological sciences · 2017-11-15 · usefulness score 42/100 · Down syndrome and Alzheimer's

Similar studies

• Synaptophysin and synaptojanin-1 in Down syndrome are differentially affected by Alzheimer's disease 2014 · Down syndrome and Alzheimer's
• Alzheimer's disease and Down's syndrome: Sharing of a unique cerebrovascular amyloid fibril protein 1984 · Down syndrome and Alzheimer's
• An investigation of the molecular mechanisms engaged before and after the development of Alzheimer disease neuropathology in Down syndrome: a proteomics approach 2014 · Down syndrome and Alzheimer's
• Dysregulation of neurotrophin signaling in the pathogenesis of Alzheimer disease and of Alzheimer disease in Down syndrome 2018 · Down syndrome and Alzheimer's
• Amyloid plaque core protein in Alzheimer disease and Down syndrome 1985 · Down syndrome and Alzheimer's
• Impaired regulation of synaptic actin cytoskeleton in Alzheimer's disease 2011 · Disease mechanisms

More on Down syndrome and Alzheimer's

• A review that covers this ground Synaptopathies: synaptic dysfunction in neurological disorders - A review from students to students Journal of neurochemistry · 2016-09-08 · usefulness score 51/100
• Newest in this subject Differential endothelial cell remodeling in Down syndrome and APP duplication drives distinct blood brain barrier dysfunction bioRxiv · 2026-10-30 · Preprint — not yet peer-reviewed · usefulness score 16/100
• Newest in this subject Memory and Plasma pTau217 Refine Prognosis in Down Syndrome Annals of neurology · 2026-10-02 · Peer-reviewed · usefulness score 47/100

See all studies in Down syndrome and Alzheimer's →