Basic Science and Pathogenesis.

Background: Dementia with Lewy Bodies (DLB) is one of the most common Alzheimer's Disease (AD)-related dementias and it is defined by the presence of abnormal cytoplasmic inclusions composed of aggregated α-synuclein (αsyn) in neuronal soma, known as Lewy bodies (LB). LB often coexists with AD type pathology such as amyloid-β (Aβ) plaques and neurofibrillary tangles containing hyperphosphorylated tau in several LB dementias, including Parkinson's Disease Dementia and Lewy Body variant AD. These co-pathologies likely represent a spectrum of various contributions of shared mechanisms that underlie these diseases.

Loss of presenilin function enhances tau phosphorylation and aggregation in mice.

Mutations in the presenilin (PS/PSEN) genes encoding the catalytic components of γ-secretase accelerate amyloid-β (Aβ) and tau pathologies in familial Alzheimer's disease (AD). Although the mechanisms by which these mutations affect Aβ are well defined, the precise role PS/γ-secretase on tau pathology in neurodegeneration independently of Aβ is largely unclear. Here we report that neuronal PS deficiency in conditional knockout (cKO) mice results in age-dependent brain atrophy, inflammatory responses and accumulation of pathological tau in neurons and glial cells.

Reversal of memory and neuropsychiatric symptoms and reduced tau pathology by selenium in 3xTg-AD mice.

Accumulation of amyloid-β plaques and tau contribute to the pathogenesis of Alzheimer's disease (AD), but it is unclear whether targeting tau pathology by antioxidants independently of amyloid-β causes beneficial effects on memory and neuropsychiatric symptoms. Selenium, an essential antioxidant element reduced in the aging brain, prevents development of neuropathology in AD transgenic mice at early disease stages. The therapeutic potential of selenium for ameliorating or reversing neuropsychiatric and cognitive behavioral symptoms at late AD stages is largely unknown.