Abstract
The role of the cerebellum in Alzheimer’s disease (AD) has been neglected for a long time. Recent studies carried out using transgenic mouse models have demonstrated that amyloid-β (Aβ) is deposited in the cerebellum and affects synaptic transmission and plasticity, sometimes before plaque formation. A wide variability of motor phenotype has been observed in the different murine models of AD, without a consistent correlation with the extent of cerebellar histopathological changes or with cognitive deficits. The loss of noradrenergic drive may contribute to the impairment of cerebellar synaptic function and motor learning observed in these mice. Furthermore, cerebellar neurons, particularly granule cells, have been used as in vitro model of Aβ-induced neuronal damage. An unexpected conclusion is that the cerebellum, for a long time thought to be somehow protected from AD pathology, is actually considered as a region vulnerable to Aβ toxic damage, even at the early stage of the disease, with consequences on motor performance.
Highlights
Accumulating evidence indicates that Alzheimer’s disease (AD) is caused by the toxicity of amyloid-β (Aβ) peptide (Haass and Selkoe, 2007; Shankar et al, 2008; Gouras et al, 2010)
Further studies in APP23 transgenic mice have shown that degeneration of locus coeruleus (LC) results in elevated Aβ deposition and increased neuroinflammation in brain areas usually innervated by LC (Heneka et al, 2010)
By exploiting the knowledge derived from single and original studies, the involvement and contribution of the cerebellum in AD are outlined for the first time
Summary
Accumulating evidence indicates that Alzheimer’s disease (AD) is caused by the toxicity of amyloid-β (Aβ) peptide (Haass and Selkoe, 2007; Shankar et al, 2008; Gouras et al, 2010). Cases of early-onset FAD, caused by mutation of presenilin-1 (PSEN1; the catalytic subunits of γ-secretase), present Purkinje cell (PC) loss as well as cerebellar deposition of Aβ and high levels of hyperphosphorylated tau (Sepulveda-Falla et al, 2011, 2014) Cerebellar atrophy is another characteristic feature of sporadic AD which affects initially the portions of the cerebellar regions connected to the default mode network, a set of highly interacting brain regions (including angular gyrus, middle temporal gyrus, precuneus and dorsal medial prefrontal cortex) involved in cognition and extensively affected by neurodegeneration such as in AD (Thomann et al, 2008; Mevel et al, 2011; Guo et al, 2016). We provide for the first time a comprehensive review of the literature regarding the cerebellar cellular and molecular characterization in mouse models of AD, that can help researchers to better understand cerebellar contribution in neurodegenerative disorders and eventually provide the basis for future research on this field
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