alpha-synuclein and Psychomotor-Agitation

Neuropsychiatric symptoms such as agitation and delusions occur frequently in Lewy body dementia and Alzheimer's disease and represent significant burden and unmet treatment need. The underlying aetiology remains poorly understood.. We used a multidimensional linear model to look for associations between measurements of agitation, delusions, amyloid, tau and α-synuclein pathology, and synaptic proteins (ZnT3, PSD95, synaptophysin, and β-III-tubulin) across multiple brain regions in post-mortem tissue from a cohort of 130 Lewy body dementia and Alzheimer's disease patients and non-demented controls.. We found both agitations and delusions to be significantly associated with increased tau pathology and decreased levels of ZnT3. ZnT3 packages Zn. Our finding adds to the evidence that zinc modulating compounds are of interest for treatment or symptomatic relief in these dementias.

Topics: Aged; Aged, 80 and over; alpha-Synuclein; Alzheimer Disease; Amyloid; Biomarkers; Blotting, Western; Brain; Cation Transport Proteins; Cohort Studies; Delusions; Female; Humans; Lewy Body Disease; Linear Models; Male; Middle Aged; Psychomotor Agitation; tau Proteins

Agitation associated with dementia is frequently reported clinically but has received little attention in preclinical models of dementia. The current study used a 7PA2 CM intracerebroventricular injection model of Alzheimer's disease (AD) to assess acute memory impairment, and a bilateral intrahippocampal (IH) injection model of AD (aggregated Aβ1-42 injections) and a bilateral IH injection model of dementia with Lewy bodies (aggregated NAC61-95 injections) to assess chronic memory impairment in the rat. An alternating-lever cyclic-ratio schedule of operant responding was used for data collection, where incorrect lever perseverations measured executive function (memory) and running response rates (RRR) measured behavioral output (agitation). The results indicate that bilateral IH injections of Aβ1-42 and bilateral IH injections of NAC61-95 decreased memory function and increased RRRs, whereas intracerebroventricular injections of 7PA2 CM decreased memory function but did not increase RRRs. These findings show that using the aggregated peptide IH injection models of dementia to induce chronic neurotoxicity, memory decline was accompanied by elevated behavioral output. This demonstrates that IH peptide injection models of dementia provide a preclinical screen for pharmacological interventions used in the treatment of increased behavioral output (agitation), which also establish detrimental side effects on memory.

Topics: alpha-Synuclein; Alzheimer Disease; Amyloid beta-Peptides; Animals; Behavior, Animal; Conditioning, Operant; Disease Models, Animal; Executive Function; Hippocampus; Injections, Intraventricular; Lewy Body Disease; Male; Memory Disorders; Peptide Fragments; Psychomotor Agitation; Rats; Rats, Sprague-Dawley

α-Synuclein (α-syn), the main component of Lewy bodies, was identified as a genetic risk factor for idiopathic Parkinson's disease (PD). As a model for PD, we generated human α-syn bacterial artificial chromosome transgenic mice (BAC tg mice) harboring the entire human α-syn gene and its gene expression regulatory regions. The α-syn BAC tg mice manifested decreased anxiety-like behaviors which may reflect non-motor symptoms of early PD, and they exhibited increased SERT expression that may be responsible for decreased anxiety-like behaviors. Our α-syn BAC tg mice could be a valuable tool to evaluate α-syn gene dosage effects in vivo.

Topics: alpha-Synuclein; Animals; Anxiety; Chromosomes, Artificial, Bacterial; Disease Models, Animal; Humans; Mice; Mice, Transgenic; Motor Activity; Parkinson Disease; Psychomotor Agitation