Alzheimer disease (AD) represents an oncoming epidemic that without an effective treatment promises to exact extraordinary human and financial burdens. Studies of pathogenesis are essential for defining targets for discovering disease-modifying treatments. Past studies of AD neuropathology provided valuable, albeit limited, insights. Nevertheless, building on these findings, recent studies have provided an increasingly rich harvest of genetic, molecular and cellular data that are creating unprecedented opportunities to both understand and treat AD. Among the most significant are those documenting the presence within the AD brain of toxic oligomeric species of Aβ and tau. Existing data support the view that such species can propagate and spread within neural circuits. To place these findings in context we first review the genetics and neuropathology of AD, including AD in Down syndrome (AD-DS). We detail studies that support the existence of toxic oligomeric species while noting the significant unanswered questions concerning their precise structures, the means by which they spread and undergo amplification and how they induce neuronal dysfunction and degeneration. We conclude by offering a speculative synthesis for how oligomers of Aβ and tau initiate and drive pathogenesis. While 100 years after Alzheimer’s first report there is much still to learn about pathogenesis and the discovery of disease-modifying treatments, the application of new concepts and sophisticated new tools are poised to deliver important advances for combatting AD.

Alzheimer disease (AD) represents an oncoming epidemic that without an effective treatment promises to exact extraordinary financial and emotional burdens (Apostolova, 2016). Studies of pathogenesis are essential for defining critical molecular and cellular events and for discovering therapies to prevent or mitigate their effects. Through studies of neuropathology, genetic and cellular, and molecular biology recent decades have provided many important insights. Several hypotheses have been suggested. Documentation in the 1980s of selective loss of cholinergic neurons of the basal forebrain, followed by clinical improvement in those treated with inhibitors of acetylycholinesterase, supported the "cholinergic hypothesis of age-related cognitive dysfunction" (Bartus et al., 1982). A second hypothesis, prompted by the selective loss of cholinergic neurons and the discovery of central nervous system (CNS) neurotrophic factors, including nerve growth factor (NGF), prompted the "deficient neurotrophic hypothesis" (Chen et al., 2018). The most persuasive hypothesis, the amyloid cascade hypothesis first proposed more than 25 years ago (Selkoe and Hardy, 2016), is supported by a wealth of observations. Genetic studies were exceptionally important, pointing to increased dose of the gene for the amyloid precursor protein (APP) in Down syndrome (DS) and a familial AD (FAD) due to duplication of APP and to mutations in APP and in the genes for Presenilin 1 and 2 (PSEN1, 2), which encode the γ-secretase enzyme that processes APP (Dorszewska et al., 2016). The "tau hypothesis" noted the prominence of tau-related pathology and its correlation with dementia (Kametani and Hasegawa, 2018). Recent interest in induction of microglial activation in the AD brain, as well as other manifestations of inflammation, supports the "inflammatory hypothesis" (Mcgeer et al., 2016). We place these findings in the context of the selective, but by no means unique, involvement of BFCNs and their trophic dependence on NGF signaling and speculate as to how pathogenesis in these neurons is initiated, amplified and ultimately results in their dysfunction and death. In so doing we attempt to show how the different hypotheses for AD may interact and reinforce one another. Finally, we address current attempts to prevent and/or treat AD in light of advances in understanding pathogenetic mechanisms and suggest that studies in the DS population may provide unique insights into AD pathogenesis and treatment.

Dominant mutations in glycyl-tRNA synthetase (GlyRS) cause a subtype of Charcot-Marie-Tooth neuropathy (CMT2D). Although previous studies have shown that GlyRS mutants aberrantly interact with Nrp1, giving insight into the disease’s specific effects on motor neurons, these cannot explain length-dependent axonal degeneration. Here, we report that GlyRS mutants interact aberrantly with HDAC6 and stimulate its deacetylase activity on α-tubulin. A decrease in α-tubulin acetylation and deficits in axonal transport are observed in mice peripheral nerves prior to disease onset. An HDAC6 inhibitor used to restore α-tubulin acetylation rescues axonal transport deficits and improves motor functions of CMT2D mice. These results link the aberrant GlyRS-HDAC6 interaction to CMT2D pathology and suggest HDAC6 as an effective therapeutic target. Moreover, the HDAC6 interaction differs from Nrp1 interaction among GlyRS mutants and correlates with divergent clinical presentations, indicating the existence of multiple and different mechanisms in CMT2D.

Early detection of gastrointestinal tumors improves patient survival. However, patients with these tumors are typically diagnosed at an advanced stage and have poor prognosis. The incidence and mortality of gastrointestinal cancers, including esophageal, gastric, liver, colorectal, and pancreatic cancers, are increasing worldwide. Novel diagnostic and therapeutic agents are required to improve patient survival and quality of life. The tumor microenvironment, which contains nontumor cells, signaling molecules such as growth factors and cytokines, and extracellular matrix proteins, plays a critical role in cancer cell proliferation, invasion, and metastasis. Transforming growth factor beta (TGF-β) signaling has dual roles in gastrointestinal tumor development and progression as both a tumor suppressor and tumor promoter. Here, we review the dynamic roles of TGF-β and its receptors in gastrointestinal tumors and provide evidence that targeting TGF-β signaling may be an effective therapeutic strategy.

Significance: Degeneration of the corticostriatal circuit is a key neuropathological and clinical feature of Huntington’s disease (HD). To define disease mechanisms and explore treatments, we recreated the corticostriatal circuit in microfluidic chambers using neurons from the BACHD mouse model of HD and WT controls. We showed that expression of mutant huntingtin (mHTT) induced defects in brain-derived neurotrophic factor (BDNF) transport in BACHD cortical axons that resulted in atrophy of striatal target neurons. Introducing subunits of the cytosolic chaperonin T-complex 1 (TCP-1) ring complex (TRiC) into BACHD cortical neurons reduced mHTT, rescued defects in BDNF transport, and normalized the size of striatal neurons. These findings encourage studies to explore a role for TRiC reagents as possible treatments for HD.

Recent studies have demonstrated that hyperphosphorylation of tau protein plays a role in neuronal toxicities of α-synuclein (ASYN) in neurodegenerative disease such as familial Alzheimer’s disease (AD), dementia with Lewy bodies (DLB) and Parkinson’s disease. Using a transgenic mouse model of Parkinson’s disease (PD) that expresses GFP-ASYN driven by the PDGF-β promoter, we investigated how accumulation of ASYN impacted axonal function. We found that retrograde axonal trafficking of brain-derived neurotrophic factor (BDNF) in DIV7 cultures of E18 cortical neurons was markedly impaired at the embryonic stage, even though hyperphosphorylation of tau was not detectable in these neurons at this stage. Interestingly, we found that overexpressed ASYN interacted with dynein and induced a significant increase in the activated levels of small Rab GTPases such as Rab5 and Rab7, both key regulators of endocytic processes. Furthermore, expression of ASYN resulted in neuronal atrophy in DIV7 cortical cultures of either from E18 transgenic mouse model or from rat E18 embryos that were transiently transfected with ASYN-GFP for 72 hrs. Our studies suggest that excessive ASYN likely alters endocytic pathways leading to axonal dysfunction in embryonic cortical neurons in PD mouse models.