Also, familial forms of Alzheimer’s disease are caused by mutations either in APP or in one of the two presenilin genes, which code for the enzymes processing APP to beta amyloid, ultimately leading to an overproduction of beta amyloid. Another line of evidence is that humans with Down syndrome develop similar pathological changes as a result of the triplication of chromosome 21, on which the amyloid precursor protein (APP) is encoded. These animal models recapitulate some but not all the typical histologic alterations such as amyloidosis, synapse and neuron loss, tau hyperphosphorylation and inflammation. This pathogenic mechanism, which is essentially covered by the amyloid cascade hypothesis, is founded on numerous animal models which are genetically engineered to develop amyloid plaques. In turn, amyloid toxicity, which may be mediated by oligomeric intermediates and/or fibrillar amyloid beta, is thought to cause tau hyperphosphorylation and inflammatory changes as endogenous reactions to the presence of noxic stimuli. These alterations are thought to be caused by an imbalance of amyloid beta production and its removal from the brain, causing the aggregation of characteristic fibrillar amyloid deposits. Quantification of these neuropathological alterations during autopsy is used today to assess whether an individual suffered from the disease now bearing Alzheimer’s name and how far the disease has progressed. He noticed distinct histological alterations in the cortex, such as fibrillary tangles inside neurons and extracellular deposits of a substance unknown to him, which has later been identified as amyloid beta. In 1906, Alois Alzheimer examined the brain of a 54-year-old woman, who had died after a three-year course of severe cognitive impairment and memory loss. Here, we critically review the most intensely studied mechanisms of spine loss in Alzheimer’s disease as well as the possible pitfalls inherent in the animal models of such a complex neurodegenerative disorder. However, to date none of these mechanisms have been translated into successful therapeutic approaches for the human disease. Lastly, genetic and therapeutic interventions employed to model the disease and elucidate its pathogenetic mechanisms in experimental animals may cause alterations of dendritic spines on their own. Furthermore, tau hyperphosphorylation and microglia activation, which are thought to be consequences of amyloidosis in Alzheimer’s disease, may also contribute to spine loss. For instance, amyloid beta fibrils, diffusible oligomers or the intracellular accumulation of amyloid beta have been found to alter the function and structure of dendritic spines by distinct mechanisms. To date, a large number of different mechanisms have been proposed to cause dendritic spine dysfunction and loss in Alzheimer’s disease. Dendritic spines are readily accessible for both in vitro and in vivo experiments and have, therefore, been studied in great detail in Alzheimer’s disease mouse models. Dendritic spines are specialized structures on neuronal processes, on which excitatory synaptic contacts take place and the loss of dendritic spines directly correlates with the loss of synaptic function. Synaptic failure is an immediate cause of cognitive decline and memory dysfunction in Alzheimer’s disease.
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