Electronic Thesis and Dissertation Repository


Doctor of Philosophy


Anatomy and Cell Biology


Whitehead, Shawn N.

2nd Supervisor

Hachinski, Vladimir



White matter integrity is crucial to healthy executive function, the cognitive domain that enables functional independence. However, in the ageing brain, white matter is highly vulnerable. White matter inflammation increases with age and Alzheimer disease (AD), which disrupts the normal function of white matter. This may contribute to executive dysfunction, but the relationship between white matter inflammation and executive function has not been directly evaluated in ageing nor AD. White matter is also particularly vulnerable to cerebrovascular disease, corresponding with the common presentation of executive dysfunction in vascular cognitive impairment (VCI). Thus, white matter may be an important substrate by which vascular injury exacerbates the cognitive impact of comorbid AD pathology and cerebrovascular pathology. To study the relationship between age, pathogenic amyloid precursor protein (APP), white matter inflammation, cerebrovascular disease, and executive dysfunction, the transgenic rat model of AD (TgAPP21) was evaluated for astrocytosis, microgliosis and cognitive impairment. The TgAPP21 rat was found to demonstrate spontaneously increased white matter microglia activation, impaired reversal learning, and a regressive impairment of behavioural flexibility, a key subdomain of executive function. The TgAPP21 rat also developed a precocious increase in white matter microglia activation. However, this was not matched by a continued increase in behavioural inflexibility, suggesting a dynamic and age-dependent relationship between white matter inflammation and behavioural flexibility. Hypertension induced by chronic angiotensin-II infusion impaired both wildtype (Wt) and TgAPP21 rats’ working memory and behavioural flexibility. However, while Wt rats demonstrated a linear increase in white matter astrocytosis in response to blood pressure elevation, normotensive TgAPP21 rats already had an increased baseline level of white matter astrocytosis and further increase in response to hypertension was not observed. TgAPP21 rats also demonstrated a greater vulnerability to cerebrovascular disease, as focal striatal ischemic injury resulted in reduced set shifting efficiency. Thus, the TgAPP21 rat is an important model for studying the complex relationship between age, pathogenic APP, and cerebrovascular disease and their impact on executive dysfunction. These findings support the emerging significance of white matter inflammation and executive dysfunction in the pathophysiology of ageing, AD, and VCI.

Wt probe.mp4 (1255 kB)
Wildtype Rat MWM Probe Test

TgAPP21 probe.mp4 (1225 kB)
TgAPP21 Rat MWM Probe Test