Epidemiological studies implicate diets rich in saturated free fatty acids (sFFA) as a potential risk factor for developing Alzheimer’s disease (AD). In particular, high plasma levels of the sFFA palmitic acid (palmitate) were shown to inversely correlate with cognitive function. However, the cellular mechanisms by which sFFA may increase the risk for AD are not well known. Endoplasmic reticulum (ER) stress has emerged as one of the signaling pathways initiating and fostering the neurodegenerative changes in AD by increasing the aspartyl protease β-site AβPP cleaving enzyme 1 (BACE1) and amyloid-β (Aβ) genesis. In this study, we determined the extent to which palmitate increases BACE1 and Aβ levels in vitro and in vivo as well as the potential role of ER stress as cellular mechanism underlying palmitate effects. We demonstrate, in palmitate-treated SH-SY5Y neuroblastoma cells and in the hippocampi of palmitate-enriched diet-fed mice, that palmitate evokes the activation of the C/EBP Homologous Protein (CHOP), a transcription factor that is specifically responsive to ER stress. Induction of CHOP expression is associated with increased BACE1 mRNA, protein and activity levels, and subsequent enhanced amyloidogenic processing of amyloid-β protein precursor (AβPP) that culminates in a substantial increase in Aβ genesis. We further show that CHOP is an indispensable molecular mediator of palmitate-induced upregulation in BACE1 activity and Aβ genesis. Indeed, we show that Chop–/– mice and CHOP knocked-down SH-SY5Y neuroblastoma cells do not exhibit the same commensurate degree of palmitate-induced increase in BACE1 expression levels and Aβ genesis.

The TDP-43 type C pathologic form of frontotemporal lobar degeneration (FTLD-TDP-type C) is characterized by the presence of immunoreactive TDP-43 short and long dystrophic neurites (DNs), neuronal cytoplasmic inclusions (NCIs), neuronal loss and gliosis (NL/G), and the absence of neuronal intranuclear inclusions (NIIs). FTLD-TDP-type C cases are commonly associated with the semantic variant of primary progressive aphasia (PPA-S) or behavioral variant frontotemporal dementia (bvFTD). Here, we provide detailed characterization of regional distributions of pathologic TDP-43 and NL/G in cortical and subcortical regions in 10 FTLD-TDP-type C cases and investigate the relationship between inclusions and NL/G. Specimens were obtained from the first 10 FTLD-TDP-type C cases accessioned from the Northwestern Alzheimer’s Disease Research Center (PPA-S, N = 7; bvFTD, N = 3). A total of 42 cortical (majority bilateral) and subcortical regions were immunostained with a phosphorylated TDP-43 antibody and/or stained with hematoxylin-eosin. Regions were evaluated for atrophy, and for long DNs, short DNs, NCIs, and NL/G using a semiquantitative 5-point scale. We calculated a “neuron-to-inclusion” score (TDP-C mean score—NL/G mean score) for each region per case to assess the relationship between TDP-type C inclusions and NL/G. PPA cases demonstrated leftward asymmetry of cortical atrophy consistent with the aphasic phenotype. We also observed abundant inclusions and neurodegeneration in both cortical and subcortical regions, with certain subcortical regions emerging as particularly vulnerable to DNs (e.g. amygdala, caudate, and putamen). Interestingly, linear mixed models showed that regions with lowest type C pathology had high neuronal dropout, and conversely, regions with abundant pathology displayed relatively preserved neuronal densities (p < 0.05). This inverse relationship between the extent of TDP-positive inclusions and neuronal loss may reflect a process whereby inclusions disappear as their associated neurons are lost. Together, these findings offer insight into the putative substrates of neurodegeneration in unique dementia syndromes.

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Background: Phosphorylated cytoplasmic tau inclusions correlate with and precede cognitive deficits in Alzheimer's disease (AD). However, pathological tau accumulation and relationships to synaptic changes remain unclear.Objective: To address this, we examined postmortem brain from 50 individuals with the full spectrum of AD (clinically and neuropathologically). Total tau, pTau231, and AMPA GluR1 were compared across two brain regions (entorhinal and middle