Synaptic loss in Alzheimer's disease and other dementias

Abstract

The extent and location of neuronal losses necessary or sufficient to produce dementia in patients with Alzheimer's Disease (AD) is unknown. To approach this question, we studied synaptic terminals in postmortem brain tissue utilizing immunohistochemical techniques. We used antibodies against two proteins found in synaptic terminals--synapsin I and synaptophysin--as synaptic markers in the hippocampal complexes of eight patients with autopsy-proven AD and eight nondemented control subjects. Quantitative microscopy measured the regional density of synaptic staining. All AD patients showed a striking decrease in synaptic staining in the outer half of the molecular layer of the dentate gyrus compared with control brains, where the density of synaptic terminals was uniform throughout. In an additional patient with progressive degenerative dementia but without plaques or tangles on neuropathologic examination, similar depletion of synaptic staining was seen in the dentate gyrus. Quantitative densitometric analyses confirmed the focal decrease in synaptic staining in the outer half of the molecular layer in demented patients. We also found a slight increase in synaptic staining in the inner half of this layer.

A high ratio of chromogranin A to synaptin/synaptophysin is a common feature of brains in Alzheimer and Pick disease

“…Its consistent low levels in Alzheimer's (which is in agreement with immunohistochemical data [19,20]) and Pick's brains can simply be an expression of neuronal and synaptic loss occurring in these diseases, but a specific loss of synaptic vesicles should also be considered. On the other hand, chromogranin A levels are increased.…”

Levels of kinesin light chain and dynein intermediate chain are reduced in the frontal cortex in Alzheimer’s disease: implications for axoplasmic transport

“…A model of KIF1B knockout mice showed reduced transport of synaptic vesicles [52]. A reduction of synaptophysin in AD brain has been reported and interpreted as evidence for synaptic loss [20,29]. We also observed this reduction of synaptophysin in the frontal cortex of AD patients.…”

Amyloid β Protein Modulates Glutamate-Mediated Neurotransmission in the Rat Basal Forebrain: Involvement of Presynaptic Neuronal Nicotinic Acetylcholine and Metabotropic Glutamate Receptors

“…Furthermore, in vitro and also in vivo experiments have shown that soluble oligomers of A␤ are capable of inhibiting LTP (Lambert et al, 1998;Walsh et al, 2002). Together, these data demonstrate the importance of soluble forms of A␤ in mediating synaptic dysfunction and correlate with neuropathological observations in brains of patients with mild cognitive impairment and AD, where synaptic disruption and loss are early pathological features (Davies et al, 1987;Hamos et al, 1989;Masliah et al, 1991). However, there is presently little information on how A␤ may influence normal synaptic transmission in the brain, particularly in structures such as the cholinergic basal forebrain that are at the epicenter of the chemical pathology seen in AD.…”